U.S. patent application number 11/766727 was filed with the patent office on 2008-12-25 for method of treating pain utilizing controlled release oxymorphone pharmaceutical compositions and instruction on dosing for hepatic impairment.
This patent application is currently assigned to Endo Pharmaceuticals, Inc.. Invention is credited to Harry Ahdieh.
Application Number | 20080318993 11/766727 |
Document ID | / |
Family ID | 40137144 |
Filed Date | 2008-12-25 |
United States Patent
Application |
20080318993 |
Kind Code |
A1 |
Ahdieh; Harry |
December 25, 2008 |
Method of Treating Pain Utilizing Controlled Release Oxymorphone
Pharmaceutical Compositions and Instruction on Dosing for Hepatic
Impairment
Abstract
The invention pertains to a method of using oxymorphone in the
treatment of pain by providing a patient with an oxymorphone dosage
form and informing the patient or prescribing physician that the
bioavailability of oxymorphone may be increased in patients with
hepatic impairment.
Inventors: |
Ahdieh; Harry; (Lincoln
University, PA) |
Correspondence
Address: |
MAYER BROWN LLP
P.O. BOX 2828
CHICAGO
IL
60690
US
|
Assignee: |
Endo Pharmaceuticals, Inc.
Chadds Ford
PA
|
Family ID: |
40137144 |
Appl. No.: |
11/766727 |
Filed: |
June 21, 2007 |
Current U.S.
Class: |
514/281 ;
424/10.2; 424/468; 705/3 |
Current CPC
Class: |
A61K 9/2059 20130101;
A61K 9/2054 20130101; G16H 20/10 20180101; A61K 31/485
20130101 |
Class at
Publication: |
514/281 ;
424/10.2; 424/468; 705/3 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/44 20060101 A61K009/44; A61K 9/22 20060101
A61K009/22 |
Claims
1-20. (canceled)
21. A method of providing extended pain relief to patients in need
thereof comprising: informing the patients or the patients'
prescribing physicians that the average bioavailability of
oxymorphone in an oral extended release dosage form designed to
have a 12 hour dosing cycle is increased by at least about 360% for
subjects with moderate hepatic impairment compared to that for
healthy subjects, providing a therapeutically effective amount of
such an extended release oral dosage form containing between about
5 mg and about 40 mg of oxymorphone or a pharmaceutically
acceptable salt thereof; and orally administering the dosage form
to the patients, wherein upon placement of the dosage form in an in
vitro dissolution test comprising USP Paddle Method at 50 rpm in
500 ml media having a pH of 1.2 to 6.8 at 37.degree. C., releases
about 15% to about 50%, by weight, of the oxymorphone or salt at
about 1 hour into the test, releases about 45% to about 80%, by
weight, of the oxymorphone or salt thereof at about 4 hours into
the test, and releases at least about 80%, by weight, of the
oxymorphone or salt thereof at about 10 hours into the test.
22. The method of claim 21 wherein in the increase in average oral
bioavailability of at least about 152% is associated with mild
hepatic impairment, and an increase in average oral bioavailability
of about 1220% is associated with severe hepatic impairment, in
each case in comparison to that for healthy subjects.
23. The method of claim 21 wherein the information is provided at
least via a label associated with the extended release oral dosage
form of oxymorphone.
24. The method of claim 21 wherein the information further contains
a recommendation that subjects with hepatic impairment be initially
administered the lowest available dose of the extended release oral
dosage form of oxymorphone or its salt.
25. The method of claim 21 wherein the information further
indicates that the half-life of the oxymorphone is not
significantly affected by hepatic impairment.
26-31. (canceled)
32. A method of providing extended pain relief to patients in need
thereof comprising: packaging an oral extended release formulation
containing between about 5 mg and about 40 mg of oxymorphone or its
pharmaceutically acceptable salt with directions that it be
administered every 12 hours and with information that the average
bioavailability of oxymorphone in an extended release formulation
designed to have a 12 hour dosing cycle is increased by at least
about 360% for subjects with moderate hepatic impairment compared
to that for healthy subjects; and orally administering to the
patients a therapeutically effective amount of said packaged
extended release formulation of oxymorphone or a pharmaceutically
acceptable salt thereof, wherein upon placement of the extended
release formulation in an in vitro dissolution test comprising USP
Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8
at 37.degree. C, releases about 15% to about 50%, by weight, of the
oxymorphone or salt at about 1 hour into the test, releases about
45% to about 80%, by weight, of the oxymorphone or salt thereof at
about 4 hours into the test, and releases at least about 80%, by
weight, of the oxymorphone or salt thereof at about 10 hours into
the test.
33. The method of claim 32 wherein in the information an increase
in average oral bioavailability of at least about 152% is
associated with mild hepatic impairment, and an increase in average
oral bioavailability of about 1220% is associated with severe
hepatic impairment, in each case in comparison to that for healthy
subjects.
34. The method of claim 32 wherein the packaged information is
provided at least via a label associated with the packaged extended
release formulation of oxymorphone.
35. The method of claim 32 wherein the directions further contain a
recommendation that patients with hepatic impairment be initially
administered the lowest available dose of the packaged extended
release formulation of oxymorphone or its salt.
36. The method of claim 32 wherein the packaged information further
indicates that the half-life of the oxymorphone is not
significantly affected by hepatic impairment.
37. The method of claim 32, wherein the ratio of the log
transformed plasma AUC of oxymorphone of an impaired patient to
that of a healthy patient is about 0.9 to about 2.5 if both
patients were administered the same dose of the formulation.
38. The method of claim 32, wherein the ratio of the log
transformed plasma C.sub.max of oxymorphone of an impaired patient
to that of a healthy patient is about 0.9 to about 2.7 if both
patients were to be administered the same dose of the
formulation.
39. The method of claim 32, wherein the ratio of the log
transformed plasma AUC of 6-OH-oxymorphone of an impaired patient
to that of a healthy patient is about 0.8 to about 2.3 if both
patients were administered the same dose of the formulation.
40. The method of claim 32, wherein the ratio of the log
transformed plasma C.sub.max of 6-OH-oxymorphone of an impaired
patient to that of a healthy patient is about 0.9 to about 2.1 if
both patients were to be administered the same dose of the
formulation.
41. A method of using oxymorphone in the treatment of pain in a
patient having mild hepatic impairment in need thereof, comprising:
providing a patient having mild hepatic impairment with a
therapeutically effective amount of a controlled release oral
dosage form containing about 5 mg to about 40 mg of oxymorphone or
a pharmaceutically acceptable salt thereof; informing the patient
or the patient's prescribing physician that the bioavailability of
oxymorphone may be increased in patients with hepatic impairment;
and orally administering the dosage form of oxymorphone to the
patient, wherein the ratio of the log transformed plasma AUC of
oxymorphone of an impaired patient to that of a healthy patient is
about 0.9 to about 2.5 if both patients were administered the same
dose of the oxymorphone or salt thereof.
Description
BACKGROUND OF THE INVENTION
[0001] Pain is the most frequently reported symptom and it is a
common clinical problem which confronts the clinician. Many
millions of people in the USA suffer from severe pain that,
according to numerous recent reports, is chronically undertreated
or inappropriately managed. The clinical usefulness of the
analgesic properties of opioids has been recognized for centuries,
and morphine and its derivatives have been widely employed for
analgesia for decades in a variety of clinical pain states.
[0002] Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride)
is a semi-synthetic phenanthrene-derivative opioid agonist, widely
used in the treatment of acute and chronic pain, with analgesic
efficacy comparable to other opioid analgesics. Oxymorphone is
currently marketed as an injection (1 mg/ml in 1 ml ampules; 1.5
mg/ml in 1 ml ampules; 1.5 mg/ml in 10 ml multiple dose vials) for
intramuscular, subcutaneous, and intravenous administration, and as
5 mg rectal suppositories. At one time, 2 mg, 5 mg and 10 mg oral
immediate release (IR) tablet formulations of oxymorphone HCl were
marketed. Oxymorphone HCl is metabolized principally in the liver
and undergoes conjugation with glucuronic acid and reduction to
6-alpha- and beta-hydroxy epimers.
[0003] An important goal of analgesic therapy is to achieve
continuous relief of chronic pain. Regular administration of an
analgesic is generally required to ensure that the next dose is
given before the effects of the previous dose have worn off.
Compliance with opioids increases as the required dosing frequency
decreases. Non-compliance results in suboptimal pain control and
poor quality of life outcomes. (Ferrell B et al. Effects of
controlled-release morphine on quality of life for cancer pain.
Oncol. Nur. Forum 1989; 4:521-26). Scheduled, rather than "as
needed" administration of opioids is currently recommended in
guidelines for their use in chronic non-malignant pain.
Unfortunately, evidence from prior clinical trials and clinical
experience suggests that the short duration of action of immediate
release oxymorphone would necessitate administration every 4-6
hours in order to maintain optimal levels of analgesia in chronic
pain. A controlled release formulation which would allow less
frequent dosing of oxymorphone would be useful in pain
management.
[0004] For instance, a controlled release formulation of morphine
has been demonstrated to provide patients fewer interruptions in
sleep, reduced dependence on caregivers, improved compliance,
enhanced quality of life outcomes, and increased control over the
management of pain. In addition, the controlled release formulation
of morphine was reported to provide more constant plasma
concentration and clinical effects, less frequent peak to trough
fluctuations, reduced dosing frequency, and possibly fewer side
effects. (Thirlwell M P et al., Pharmacokinetics and clinical
efficacy of oral morphine solution and controlled-release morphine
tablets in cancer patients. Cancer 1989; 63:2275-83; Goughnour B R
et al., Analgesic response to single and multiple doses of
controlled-release morphine tablets and morphine oral solution in
cancer patients. Cancer 1989; 63:2294-97; Ferrell B. et al.,
Effects of controlled-release morphine on quality of life for
cancer pain. Oncol. Nur. Forum 1989; 4:521-26.
[0005] There are two factors associated with the metabolism of some
drugs that may present problems for their use in controlled release
systems. One is the ability of the drug to induce or inhibit enzyme
synthesis, which may result in a fluctuating drug blood plasma
level with chronic dosing. The other is a fluctuating drug blood
level due to intestinal (or other tissue) metabolism or through a
hepatic first-pass effect.
[0006] Oxymorphone is metabolized principally in the liver,
resulting in an oral bioavailability of about 10%. Evidence from
clinical experience suggests that the short duration of action of
immediate release oxymorphone necessitates a four hour dosing
schedule to maintain optimal levels of analgesia. It would be
useful to clinicians and patients alike to have controlled release
dosage forms of oxymorphone to use to treat pain and a method of
treating pain using the dosage forms.
[0007] Diseases of the liver can cause impaired liver function.
Examples of such diseases include hepatitis (of any type),
alcoholic liver disease, toxic liver disease, and numerous others.
Impaired liver function reduces the ability of the liver to
process, among other things, some drugs, particularly some of those
that are metabolized in the liver.
SUMMARY OF THE INVENTION
[0008] One aspect of the invention is a method of using oxymorphone
in the treatment of pain comprising providing a patient with a
therapeutically effective amount of oxymorphone, and informing the
patient or the patient's prescribing physician that the
bioavailability of oxymorphone may be increased in patients with
hepatic impairment.
[0009] Another aspect of the invention provides a method of using
oxymorphone in the treatment of pain in a patient having mild
hepatic impairment in need thereof comprising providing a patient
having mild hepatic impairment with a therapeutically effective
amount of an oral dosage form of oxymorphone, informing the patient
or the patient's prescribing physician that the bioavailability of
oxymorphone may be increased in patients with hepatic impairment,
and orally administering the dosage form of oxymorphone to the
patient.
[0010] A further aspect of the invention provides a method of using
oxymorphone in the treatment of pain in a patient having mild
hepatic impairment in need thereof comprising providing a patient
having mild hepatic impairment with a therapeutically effective
amount of a controlled release oral dosage form of oxymorphone,
informing the patient or the patient's prescribing physician that
the bioavailability of oxymorphone may be increased in patients
with hepatic impairment, and orally administering the dosage form
of oxymorphone to the patient, wherein the ratio of the log
transformed plasma AUC of oxymorphone of an impaired patient to
that of a healthy patient is about 0.9 to about 2.5 if both
patients were administered the same dose of the composition.
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIG. 1 is a pharmacokinetic profile for 6-hydroxy
oxymorphone with PID scores.
[0012] FIG. 2 is a pharmacokinetic profile for oxymorphone with PID
scores.
[0013] FIG. 3 is a pharmacokinetic profile for 6-hydroxy
oxymorphone with categorical pain scores.
[0014] FIG. 4 is a pharmacokinetic profile for oxymorphone with
categorical pain scores.
[0015] FIG. 5 is a graph of the mean blood plasma concentration of
oxymorphone versus time for clinical study 1.
[0016] FIG. 6 is a graph of the mean blood plasma concentration of
oxymorphone versus time for clinical study 2.
[0017] FIG. 7 is a graph of the mean blood plasma concentration of
oxymorphone versus time for clinical study 3.
[0018] FIG. 8 is a graph of the mean blood plasma concentration of
6-hydroxy oxymorphone versus time for clinical study 3.
[0019] FIG. 9 is a graph of the mean blood plasma concentration of
oxymorphone for immediate and controlled release tablets from a
single dose study.
[0020] FIG. 10 is a graph of the mean blood plasma concentration of
oxymorphone for immediate and controlled release tablets from a
steady state study.
[0021] FIG. 11 is a graph of mean plasma concentrations of
oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide
[0022] FIG. 12 is a graph of the ratio and 90% confidence limits
for comparison of hepatically impaired to healthy controls for
oxymorphone.
[0023] FIG. 13 is a graph of the ratio and 90% confidence limits
for comparison of hepatically impaired to healthy controls for
6-OH-oxymorphone.
[0024] FIG. 14 is a graph of the ratio and 90% confidence limits
for comparison of hepatically impaired to healthy controls for
oxymorphone-3-glucuronide.
[0025] FIG. 15 is a graph of the mean ratio (SE) of plasma
metabolite AUC to oxymorphone AUC.
[0026] FIG. 16 is a graph of cumulative urinary excretion of
oxymorphone and metabolites (by percent of administered dose).
[0027] FIG. 17 is a graph of the urinary excretion rate (nmol/hr)
of oxymorphone and metabolites.
[0028] FIG. 18 is a graph of the relationship between oxymorphone
oral clearance and measures of hepatic function.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention provides methods of using oxymorphone
in the treatment of pain. In one aspect of the invention the method
may involve steps of providing a patient with a therapeutically
effective amount of oxymorphone, and informing the patient or the
patient's prescribing physician that the bioavailability of
oxymorphone may be increased in patients with hepatic
impairment.
[0030] Among the controlled (or extended) release, as well as
immediate release, pharmaceutical compounds comprising oxymorphone
that may be used in the methods of this invention is Opana.RTM.,
which upon its approval on Jun. 22, 2006 became the first-ever
controlled release oxymorphone formulation to be approved by the
United States Food and Drug Administration (FDA). Opana.RTM. is
available in both immediate release and controlled or extended
release dosage forms. The approved labels of Opana.RTM. are
incorporated herein by reference to the extent permitted by
law.
[0031] The present invention also provides methods for alleviating
pain for 12 to 24 hours using a single dose of a pharmaceutical
composition by producing a blood plasma level of oxymorphone and/or
6-OH oxymorphone of at least a minimum value for at least 12 hours
or more. As used herein, the terms "6-OH oxymorphone" and
"6-hydroxy oxymorphone" are interchangeable and refer to the analog
of oxymorphone having an alcohol (hydroxy) moiety that replaces the
carboxy moiety found on oxymorphone at the 6-position.
[0032] To overcome the difficulties associated with a 4-6 hourly
dosing frequency of oxymorphone, this invention provides an
oxymorphone controlled release oral solid dosage form, comprising a
therapeutically effective amount of oxymorphone or a
pharmaceutically acceptable salt of oxymorphone. It has been found
that the decreased rate of release of oxymorphone from the oral
controlled release formulation of this invention does not
substantially decrease the bioavailability of the drug as compared
to the same dose of a solution of oxymorphone administered orally.
The bioavailability is sufficiently high and the release rate is
such that a sufficient plasma level of oxymorphone and/or 6-OH
oxymorphone is maintained to allow the controlled release dosage to
be used to treat patients suffering moderate to severe pain with
once or twice daily dosing. The dosing form of the present
invention can also be used with thrice daily dosing.
[0033] It is critical when considering the present invention that
the difference between a controlled release tablet and an immediate
release formulation be fully understood. In classical terms, an
immediate release formulation releases at least 80% of its active
pharmaceutical ingredient within 30 minutes. With reference to the
present invention, the definition of an immediate release
formulation will be broadened further to include a formulation
which releases more than about 80% of its active pharmaceutical
ingredient within 60 minutes in a standard USP Paddle Method
dissolution test at 50 rpm in 500 ml media having a pH of between
1.2 and 6.8 at 37.degree. C. "Controlled release" formulations, as
referred to herein, will then encompass any formulations which
release no more than about 80% of their active pharmaceutical
ingredients within 60 minutes under the same conditions.
[0034] The controlled release dosage form of this invention
exhibits a dissolution rate in vitro, when measured by USP Paddle
Method at 50 rpm in 500 ml media having a pH between 1.2 and 6.8 at
37.degree. C., of about 15% to about 50% by weight oxymorphone
released after 1 hour, about 45% to about 80% by weight oxymorphone
released after 4 hours, and at least about 80% by weight
oxymorphone released after 10 hours.
[0035] When administered orally to humans, an effective controlled
release dosage form of oxymorphone should exhibit the following in
vivo characteristics: (a) peak plasma level of oxymorphone occurs
within about 1 to about 8 hours after administration; (b) peak
plasma level of 6-OH oxymorphone occurs within about 1 to about 8
hours after administration; (c) duration of analgesic effect is
through about 8 to about 24 hours after administration; (d)
relative oxymorphone bioavailability is in the range of about 0.5
to about 1.5 compared to an orally-administered aqueous solution of
oxymorphone; and (e) the ratio of the area under the curve of blood
plasma level vs. time for 6-OH oxymorphone compared to oxymorphone
is in the range of about 0.5 to about 1.5. Of course, there is
variation of these parameters among subjects, depending on the size
and weight of the individual subject, the subject's age, individual
metabolism differences, and other factors. Indeed, the parameters
may vary in an individual from day to day. Accordingly, the
parameters set forth above are intended to be mean values from a
sufficiently large study so as to minimize the effect of individual
variation in arriving at the values. A convenient method for
arriving at such values is by conducting a study in accordance with
standard FDA procedures such as those employed in producing results
for use in a new drug application (or abbreviated new drug
application) before the FDA. Any reference to mean values herein,
in conjunction with desired results, refer to results from such a
study, or some comparable study. Reference to mean values reported
herein for studies actually conducted are arrived at using standard
statistical methods as would be employed by one skilled in the art
of pharmaceutical formulation and testing for regulatory
approval.
[0036] In one specific embodiment of the controlled release matrix
form of the invention, the oxymorphone or salt of oxymorphone is
dispersed in a controlled release delivery system that comprises a
hydrophilic material which, upon exposure to gastrointestinal
fluid, forms a gel matrix that releases oxymorphone at a controlled
rate. The rate of release of oxymorphone from the matrix depends on
the drug's partition coefficient between components of the matrix
and the aqueous phase within the gastrointestinal tract. In a
preferred form of this embodiment, the hydrophilic material of the
controlled release delivery system comprises a mixture of a
heteropolysaccharide gum and an agent capable of cross-linking the
heteropolysaccharide in presence of gastrointestinal fluid. The
controlled release delivery system may also comprise a
water-soluble pharmaceutical diluent mixed with the hydrophilic
material. Preferably, the cross-linking agent is a
homopolysaccharide gum and the inert pharmaceutical diluent is a
monosaccharide, a disaccharide, or a polyhydric alcohol, or a
mixture thereof.
[0037] In a specific preferred embodiment, the appropriate blood
plasma levels of oxymorphone and 6-hydroxy oxymorphone are achieved
using oxymorphone in the form of oxymorphone hydrochloride, wherein
the weight ratio of heteropolysaccharide to homopolysaccharide is
in the range of about 1:3 to about 3:1, the weight ratio of
heteropolysaccharide to diluent is in the range of about 1:8 to
about 8:1, and the weight ratio of heteropolysaccharide to
oxymorphone hydrochloride is in the range of about 10:1 to about
1:10. A preferred heteropolysaccharide is xanthan gum and a
preferred homopolysaccharide is locust bean gum. The dosage form
also comprises a cationic cross-linking agent and a hydrophobic
polymer. In the preferred embodiment, the dosage form is a tablet
containing about 5 mg to about 80 mg of oxymorphone hydrochloride.
In a most preferred embodiment, the tablet contains about 20 mg
oxymorphone hydrochloride.
[0038] The invention includes a method which comprises achieving
appropriate blood plasma levels of drug while providing extended
pain relief by administering one to three times per day to a
patient suffering moderate to severe, acute or chronic pain, an
oxymorphone controlled release oral solid dosage form of the
invention in an amount sufficient to alleviate the pain for a
period of about 8 hours to about 24 hours. This type and intensity
of pain is often associated with cancer, autoimmune diseases,
infections, surgical and accidental traumas and osteoarthritis.
[0039] The invention also includes a method of making an
oxymorphone controlled release oral solid dosage form of the
invention which comprises mixing particles of oxymorphone or a
pharmaceutically acceptable salt of oxymorphone with granules
comprising the controlled release delivery system, preferably
followed by directly compressing the mixture to form tablets.
[0040] Pharmaceutically acceptable salts of oxymorphone which can
be used in this invention include salts with the inorganic and
organic acids which are commonly used to produce nontoxic salts of
medicinal agents. Illustrative examples would be those salts formed
by mixing oxymorphone with hydrochloric, sulfuric, nitric,
phosphoric, phosphorous, hydrobromic, maleric, malic, ascorbic,
citric or tartaric, pamoic, lauric, stearic, palmitic, oleic,
myristic, lauryl sulfuric, naphthylenesulfonic, linoleic or
linolenic acid, and the like. The hydrochloride salt is
preferred.
[0041] It has now been found that 6-OH oxymorphone, which is one of
the metabolites of oxymorphone, may play a role in alleviating
pain. When oxymorphone is ingested, part of the dosage gets into
the bloodstream to provide pain relief, while another part is
metabolized to 6-OH oxymorphone. This metabolite then enters the
bloodstream to provide further pain relief. Thus it is believed
that both the oxymorphone and 6-hydroxyoxymorphone levels are
important to pain relief.
[0042] The effectiveness of oxymorphone and 6-hydroxyoxymorphone at
relieving pain and the pharmacokinetics of a single dose of
oxymorphone were studied. The blood plasma levels of both
oxymorphone and 6-hydroxyoxymorphone were measured in patients
after a single dose of oxymorphone was administered. Similarly, the
pain levels in patients were measured after a single administration
of oxymorphone to determine the effective duration of pain relief
from a single dose. FIGS. 1-2 show the results of these tests,
comparing pain levels to oxymorphone and 6-hydroxy oxymorphone
levels.
[0043] For these tests, pain was measured using a Visual Analog
Scale (VAS) or a Categorical Scale. The VAS scales consisted of a
horizontal line, 100 mm in length. The left-hand end of the scale
(0 mm) was marked with the descriptor "No Pain" and the right-hand
end of the scale (100 mm) was marked with the descriptor "Extreme
Pain". Patients indicated their level of pain by making a vertical
mark on the line. The VAS score was equal to the distance (in mm)
from the left-hand end of the scale to the patient's mark. For the
categorical scale, patients completed the following statement, "My
pain at this time is" using the scale None=0, Mild=1, Moderate=2,
or Severe=3.
[0044] As can be seen from these figures, there is a correlation
between pain relief and both oxymorphone and 6-hydroxyoxymorphone
levels. As the blood plasma levels of oxymorphone and
6-hydroxyoxymorphone increase, pain decreases (and pain intensity
difference and pain relief increases). Thus, to the patient, it is
the level of oxymorphone and 6-hydroxyoxymorphone in the blood
plasma which is most important. Further it is these levels which
dictate the efficacy of the dosage form. A dosage form which
maintains a sufficiently high level of oxymorphone or
6-hydroxyoxymorphone for a longer period need not be administered
frequently. Such a result is accomplished by embodiments of the
present invention.
[0045] The oxymorphone controlled release oral solid dosage form of
this invention can be made using any of several different
techniques for producing controlled release oral solid dosage forms
of opioid analgesics.
[0046] In one embodiment, a core comprising oxymorphone or
oxymorphone salt is coated with a controlled release film which
comprises a water insoluble material and which upon exposure to
gastrointestinal fluid releases oxymorphone from the core at a
controlled rate. In a second embodiment, the oxymorphone or
oxymorphone salt is dispersed in a controlled release delivery
system that comprises a hydrophilic material which upon exposure to
gastrointestinal fluid forms a gel matrix that releases oxymorphone
at a controlled rate. A third embodiment is a combination of the
first two: a controlled release matrix coated with a controlled
release film. In a fourth embodiment the oxymorphone is
incorporated into an osmotic pump. In any of these embodiments, the
dosage form can be a tablet, a plurality of granules in a capsule,
or other suitable form, and can contain lubricants, colorants,
diluents, and other conventional ingredients.
[0047] Osmotic Pump
[0048] An osmotic pump comprises a shell defining an interior
compartment and having an outlet passing through the shell. The
interior compartment contains the active pharmaceutical ingredient.
Generally the active pharmaceutical ingredient is mixed with
excipients or other compositions such as a polyalkylene. The shell
is generally made, at least in part, from a material (such as
cellulose acetate) permeable to the liquid of the environment where
the pump will be used, usually stomach acid. Once ingested, the
pump operates when liquid diffuses through the shell of the pump.
The liquid dissolves the composition to produce a saturated
situation. As more liquid diffuses into the pump, the saturated
solution containing the pharmaceutical is expelled from the pump
through the outlet. This produces a nearly constant release of
active ingredient, in the present case, oxymorphone.
[0049] Controlled Release Coating
[0050] In this embodiment, a core comprising oxymorphone or
oxymorphone salt is coated with a controlled release film which
comprises a water insoluble material. The film can be applied by
spraying an aqueous dispersion of the water insoluble material onto
the core. Suitable water insoluble materials include alkyl
celluloses, acrylic polymers, waxes (alone or in admixture with
fatty alcohols), shellac and zein. The aqueous dispersions of alkyl
celluloses and acrylic polymers preferably contain a plasticizer
such as triethyl citrate, dibutyl phthalate, propylene glycol, and
polyethylene glycol. The film coat can contain a water-soluble
material such as polyvinylpyrrolidone (PVP) or
hydroxypropylmethylcellulose (HPMC).
[0051] The core can be a granule made, for example, by wet
granulation of mixed powders of oxymorphone or oxymorphone salt and
a binding agent such as HPMC, or by coating an inert bead with
oxymorphone or oxymorphone salt and a binding agent such as HPMC,
or by spheronising mixed powders of oxymorphone or oxymorphone salt
and a spheronising agent such as microcrystalline cellulose. The
core can be a tablet made by compressing such granules or by
compressing a powder comprising oxymorphone or oxymorphone
salt.
[0052] The in vitro and in vivo release characteristics of this
controlled release dosage form can be modified by using mixtures of
different water insoluble and water soluble materials, using
different plasticizers, varying the thickness of the controlled
release film, including release-modifying agents in the coating, or
by providing passageways through the coating.
[0053] Controlled Release Matrix
[0054] It is important in the present invention that appropriate
blood plasma levels of oxymorphone and 6-hydroxy oxymorphone be
achieved and maintained for sufficient time to provide pain relief
to a patient for a period of 12 to 24 hours. The preferred
composition for achieving and maintaining the proper blood plasma
levels is a controlled-release matrix. In this embodiment, the
oxymorphone or oxymorphone salt is dispersed in a controlled
release delivery system that comprises a hydrophilic material
(gelling agent) which upon exposure to gastrointestinal fluid forms
a gel matrix that releases oxymorphone at a controlled rate. Such
hydrophilic materials include gums, cellulose ethers, acrylic
resins, and protein-derived materials. Suitable cellulose ethers
include hydroxyalkyl celluloses and carboxyalkyl celluloses,
especially hydroxyethyl cellulose (HEC), hydroxypropyl cellulose
(HPC), HPMC, and carboxy methylcellulose (CMC). Suitable acrylic
resins include polymers and copolymers of acrylic acid, methacrylic
acid, methyl acrylate and methyl methacrylate. Suitable gums
include heteropolysaccharide and homopolysaccharide gums, e.g.,
xanthan, tragacanth, acacia, karaya, alginates, agar, guar,
hydroxypropyl guar, carrageenan, and locust bean gums.
[0055] Preferably, the controlled release tablet of the present
invention is formed from (I) a hydrophilic material comprising (a)
a heteropolysaccharide; or (b) a heteropolysaccharide and a
cross-linking agent capable of cross-linking said
heteropolysaccharide; or (c) a mixture of (a), (b) and a
polysaccharide gum; and (II) an inert pharmaceutical filler
comprising up to about 80% by weight of the tablet; and (III)
oxymorphone.
[0056] The term "heteropolysaccharide" as used herein is defined as
a water-soluble polysaccharide containing two or more kinds of
sugar units, the heteropolysaccharide having a branched or helical
configuration, and having excellent water-wicking properties and
immense thickening properties.
[0057] A preferred heteropolysaccharide is xanthan gum, which is a
high molecular weight (>10.sup.6) heteropolysaccharide. Other
preferred heteropolysaccharides include derivatives of xanthan gum,
such as deacylated xanthan gum, the carboxymethyl ether, and the
propylene glycol ester.
[0058] The cross linking agents used in the controlled release
embodiment of the present invention which are capable of
cross-linking with the heteropolysaccharide include
homopolysaccharide gums such as the galactomannans, i.e.,
polysaccharides which are composed solely of mannose and galactose.
Galactomannans which have higher proportions of unsubstituted
mannose regions have been found to achieve more interaction with
the heteropolysaccharide. Locust bean gum, which has a higher ratio
of mannose to the galactose, is especially preferred as compared to
other galactomannans such as guar and hydroxypropyl guar.
[0059] Preferably, the ratio of heteropolysaccharide to
homopolysaccharide is in the range of about 1:9 to about 9:1,
preferably about 1:3 to about 3:1. Most preferably, the ratio of
xanthan gum to polysaccharide material (i.e., locust bean gum,
etc.) is preferably about 1:1.
[0060] In addition to the hydrophilic material, the controlled
release delivery system can also contain an inert pharmaceutical
diluent such as a monosaccharide, a disaccharide, a polyhydric
alcohol and mixtures thereof. The ratio of diluent to hydrophilic
matrix-forming material is generally in the range of about 1:3 to
about 3:1.
[0061] The controlled release properties of the controlled release
embodiment of the present invention may be optimized when the ratio
of heteropolysaccharide gum to homopolysaccharide material is about
1:1, although heteropolysaccharide gum in an amount of from about
20 to about 80% or more by weight of the heterodisperse
polysaccharide material provides an acceptable slow release
product. The combination of any homopolysaccharide gums known to
produce a synergistic effect when exposed to aqueous solutions may
be used in accordance with the present invention. It is also
possible that the type of synergism which is present with regard to
the gum combination of the present invention could also occur
between two homogeneous or two heteropolysaccharides. Other
acceptable gelling agents which may be used in the present
invention include those gelling agents well-known in the art.
Examples include vegetable gums such as alginates, carrageenan,
pectin, guar gum, xanthan gum, modified starch,
hydroxypropylmethylcellulose, methylcellulose, and other cellulosic
materials such as sodium carboxymethylcellulose and hydroxypropyl
cellulose. This list is not meant to be exclusive.
[0062] The combination of xanthan gum with locust bean gum with or
without the other homopolysaccharide gums is an especially
preferred gelling agent. The chemistry of certain of the
ingredients comprising the excipients of the present invention such
as xanthan gum is such that the excipients are considered to be
self-buffering agents which are substantially insensitive to the
solubility of the medicament and likewise insensitive to the pH
changes along the length of the gastrointestinal tract.
[0063] The inert filler of the sustained release excipient
preferably comprises a pharmaceutically acceptable saccharide,
including a monosaccharide, a disaccharide, or a polyhydric
alcohol, and/or mixtures of any of the foregoing. Examples of
suitable inert pharmaceutical fillers include sucrose, dextrose,
lactose, microcrystalline cellulose, fructose, xylitol, sorbitol,
mixtures thereof and the like. However, it is preferred that a
soluble pharmaceutical filler such as lactose, dextrose, sucrose,
or mixtures thereof be used.
[0064] The cationic cross-linking agent which is optionally used in
conjunction with the controlled release embodiment of the present
invention may be monovalent or multivalent metal cations. The
preferred salts are the inorganic salts, including various alkali
metal and/or alkaline earth metal sulfates, chlorides, borates,
bromides, citrates, acetates, lactates, etc. Specific examples of
suitable cationic cross-linking agents include calcium sulfate,
sodium chloride, potassium sulfate, sodium carbonate, lithium
chloride, tripotassium phosphate, sodium borate, potassium bromide,
potassium fluoride, sodium bicarbonate, calcium chloride, magnesium
chloride, sodium citrate, sodium acetate, calcium lactate,
magnesium sulfate and sodium fluoride. Multivalent metal cations
may also be utilized. However, the preferred cationic cross-linking
agents are bivalent. Particularly preferred salts are calcium
sulfate and sodium chloride. The cationic cross-linking agents of
the present invention are added in an amount effective to obtain a
desirable increased gel strength due to the cross-linking of the
gelling agent (e.g., the heteropolysaccharide and
homopolysaccharide gums). In preferred embodiments, the cationic
cross-linking agent is included in the sustained release excipient
of the present invention in an amount from about 1 to about 20% by
weight of the sustained release excipient, and in an amount about
0.5% to about 16% by weight of the final dosage form.
[0065] In the controlled release embodiments of the present
invention, the sustained release excipient comprises from about 10
to about 99% by weight of a gelling agent comprising a
heteropolysaccharide gum and a homopolysaccharide gum, from about 1
to about 20% by weight of a cationic crosslinking agent, and from
about 0 to about 89% by weight of an inert pharmaceutical diluent.
In other embodiments, the sustained release excipient comprises
from about 10 to about 75% gelling agent, from about 2 to about 15%
cationic crosslinking agent, and from about 30 to about 75% inert
diluent. In yet other embodiments, the sustained release excipient
comprises from about 30 to about 75% gelling agent, from about 5 to
about 10% cationic cross-linking agent, and from about 15 to about
65% inert diluent.
[0066] The sustained release excipient used in this embodiment of
the present invention (with or without the optional cationic
cross-linking agent) may be further modified by incorporation of a
hydrophobic material which slows the hydration of the gums without
disrupting the hydrophilic matrix. This is accomplished in
preferred embodiments of the present invention by granulating the
sustained release excipient with the solution or dispersion of a
hydrophobic material prior to the incorporation of the medicament.
The hydrophobic polymer may be selected from an alkylcellulose such
as ethylcellulose, other hydrophobic cellulosic materials, polymers
or copolymers derived from acrylic or methacrylic acid esters,
copolymers of acrylic and methacrylic acid esters, zein, waxes,
shellac, hydrogenated vegetable oils, and any other
pharmaceutically acceptable hydrophobic material known to those
skilled in the art. The amount of hydrophobic material incorporated
into the sustained release excipient is that which is effective to
slow the hydration of the gums without disrupting the hydrophilic
matrix formed upon exposure to an environmental fluid. In certain
preferred embodiments of the present invention, the hydrophobic
material is included in the sustained release excipient in an
amount from about 1 to about 20% by weight. The solvent for the
hydrophobic material may be an aqueous or organic solvent, or
mixtures thereof.
[0067] Examples of commercially available alkylcelluloses are
Aquacoat coating (aqueous dispersion of ethylcellulose available
from FMC of Philadelphia, Pa.) and Surelease coating (aqueous
dispersion of ethylcellulose available from Colorcon of West Point,
Pa.). Examples of commercially available acrylic polymers suitable
for use as the hydrophobic material include Eudragit RS and RL
polymers (copolymers of acrylic and methacrylic acid esters having
a low content (e.g., 1:20 or 1:40) of quaternary ammonium compounds
available from Rohm America of Piscataway, N.J.).
[0068] The controlled release matrix useful in the present
invention may also contain a cationic cross-linking agent such as
calcium sulfate in an amount sufficient to cross-link the gelling
agent and increase the gel strength, and an inert hydrophobic
material such as ethyl cellulose in an amount sufficient to slow
the hydration of the hydrophilic material without disrupting it.
Preferably, the controlled release delivery system is prepared as a
pre-manufactured granulation.
[0069] It has now been discovered that the bioavailability of
controlled-release oxymorphone is increased in patients with
hepatic impairment (impaired liver function). Because of this, the
oxymorphone levels in the blood of a patient with such hepatic
impairment are higher than the levels that would be seen in a
healthy patient receiving the same dose. As such, in order to avoid
potential harmful effects, it is important to decrease the dose of
controlled-release oxymorphone in patients with impaired liver
function.
[0070] Since it is important that a patient or physician is aware
that the bioavailability is increased so as to avoid possible
issues in dosing, one embodiment of the invention comprises
informing the patient or the prescribing physician that the
bioavailability of oxymorphone may be increased in patients with
hepatic impairment. Another embodiment of the invention comprises
providing the patient or the patient's prescribing physician with
prescribing information comprising instructions for dosing the
controlled release oxymorphone composition to patients with hepatic
impairment. For example, such instructions could be included in the
labeling information, which can be for example the FDA-approved
labeling, a package insert, or on the label itself. Other ways of
communicating with patients or physicians are also available and
are contemplated by the present invention. In another embodiment,
the instructions provided comprise instructions to administer the
lowest available dose. In a further embodiment, the patient or
physician may be informed that the half life of oxymorphone is not
significantly affected by hepatic impairment
EXAMPLES
Example 1
[0071] Two controlled release delivery systems are prepared by dry
blending xanthan gum, locust bean gum, calcium sulfate dehydrate,
and dextrose in a high speed mixed/granulator for 3 minutes. A
slurry is prepared by mixing ethyl cellulose with alcohol. While
running choppers/impellers, the slurry is added to the dry blended
mixture, and granulated for another 3 minutes. The granulation is
then dried to a LOD (loss on drying) of less than about 10% by
weight. The granulation is then milled using 20 mesh screen. The
relative quantities of the ingredients are listed in the table
below.
TABLE-US-00001 TABLE 1 Cotrolled Release Delivery System
Formulation 1 Formulation 2 Excipient (%) (%) Locust Bean Gum, FCC
25.0 30.0 Xanthan Gum, NF 25.0 30.0 Dextrose, USP 35.0 40.0 Calcium
Sulfate Dihydrate, NF 10.0 0.0 Ethylcellulose, NF 5.0 0.0 Alcohol,
SD3A (Anhydrous) (10).sup.1 (20.0).sup.1 Total 100.0 100.0
[0072] A series of tablets containing different amounts of
oxymorphone hydrochloride were prepared using the controlled
release delivery Formulation 1 shown in Table 1. The quantities of
ingredients per tablet are as listed in the following table.
TABLE-US-00002 TABLE 2 Sample Tablets of Differing Strengths
Component Amounts in Tablet (mg) Oxymorphone HCl, 5 10 20 40 80 USP
(mg) Controlled release 160 160 160 160 160 delivery system
Silicified 20 20 20 20 20 microcrystalline cellulose, N.F. Sodium
stearyl 2 2 2 2 2 fumarate, NF Total weight 187 192 202 222 262
Opadry (colored) 7.48 7.68 8.08 8.88 10.48 Opadry (clear) 0.94 0.96
1.01 1.11 1.31
Examples 2, 3 and 4
[0073] Two batches of 20 mg tablets were prepared as described
above, using the controlled release delivery system of Formulation
1. One batch was formulated to provide relatively fast controlled
release, the other batch was formulated to provide relatively slow
controlled release. Compositions of the tablets are shown in the
following table.
TABLE-US-00003 TABLE 3 Slow and Fast Release Compositions Example 2
Example 3 Example 4 Ingredients Slow (mg) Fast (mg) Fast (mg)
Oxymorphone HCl, USP 20 20 20 Controlled Release Delivery System
360 160 160 Silicified Microcrystalline Cellulose, 20 20 20 NF
Sodium stearyl fumarate, NF 4 2 2 Total weight 404 202 202 Coating
(color or clear) 12 12 9
[0074] The tablets of Examples 2, 3, and 4 were tested for in vitro
release rate according to USP Procedure Drug Release U.S. Pat. No.
23. Release rate is a critical variable in attempting to control
the blood plasma levels of oxymorphone and 6-hydroxyoxymorphone in
a patient. Results are shown in the following Table 4.
TABLE-US-00004 TABLE 4 Release Rates of Slow and Fast Release
Tablets Example 2 Example 3 Example 4 Time (hr) (Slow Release)
(Fast Release) (Fast Release) 0.5 18.8 21.3 20.1 1 27.8 32.3 31.7 2
40.5 47.4 46.9 3 50.2 58.5 57.9 4 58.1 66.9 66.3 5 64.7 73.5 74.0 6
70.2 78.6 83.1 8 79.0 86.0 92.0 10 85.3 90.6 95.8 12 89.8 93.4 97.3
Clinical Studies
[0075] Three clinical studies were conducted to assess the
bioavailability (rate and extent of absorption) of oxymorphone.
Study 1 addressed the relative rates of absorption of controlled
release (CR) oxymorphone tablets (of Examples 2 and 3) and oral
oxymorphone solution in fasted patients. Study 2 addressed the
relative rates of absorption of CR oxymorphone tablets (of Examples
2 and 3) and oral oxymorphone solution in fed patients. Study 3
addressed the relative rates of absorption of CR oxymorphone
tablets (of Example 4) and oral oxymorphone solution in fed and
fasted patients.
[0076] The blood plasma levels set forth herein as appropriate to
achieve the objects of the present invention are mean blood plasma
levels. As an example, if the blood plasma level of oxymorphone in
a patient 12 hours after administration of a tablet is said to be
at least 0.5 ng/ml, any particular individual may have lower blood
plasma levels after 12 hours. However, the mean minimum
concentration should meet the limitation set forth. To determine
mean parameters, a study should be performed with a minimum of 8
adult subjects, in a manner acceptable for filing an application
for drug approval with the US Food and Drug Administration. In
cases where large fluctuations are found among patients, further
testing may be necessary to accurately determine mean values.
[0077] For all studies, the following procedures were followed,
unless otherwise specified for a particular study.
[0078] The subjects were not to consume any alcohol-, caffeine-, or
xanthine-containing foods or beverages for 24 hours prior to
receiving study medication for each study period. Subjects were to
be nicotine and tobacco free for at least 6 months prior to
enrolling in the study. In addition, over-the-counter medications
were prohibited 7 days prior to dosing and during the study.
Prescription medications were not allowed 14 days prior to dosing
and during the study.
[0079] Pharmacokinetic and Statistical Methods
[0080] The following pharmacokinetic parameters were computed from
the plasma oxymorphone concentration-time data:
[0081] AUC.sub.(0-t) Area under the drug concentration-time curve
from time zero to the time of the last quantifiable concentration
(Ct), calculated using linear trapezoidal summation.
[0082] AUC.sub.(0-inf) Area under the drug concentration-time curve
from time zero to infinity.
AUC.sub.(0-inf)=AUC.sub.(0-t)+Ct/K.sub.el, where K.sub.el is the
terminal elimination rate constant.
[0083] AUC.sub.(0-24) Partial area under the drug
concentration-time curve from time zero to 24 hours.
[0084] C.sub.max Maximum observed drug concentration.
[0085] T.sub.max Time of the observed maximum drug
concentration.
[0086] K.sub.el Elimination rate constant based on the linear
regression of the terminal linear portion of the LN (concentration)
time curve.
[0087] Terminal elimination rate constants for use in the above
calculations were in turn computed using linear regression of a
minimum of three time points, at least two of which were
consecutive. K.sub.el values for which correlation coefficients
were less than or equal to 0.8 were not reported in the
pharmacokinetic parameter tables or included in the statistical
analysis. Thus AUC.sub.(0-inf) was also not reported in these
cases.
[0088] A parametric (normal-theory) general linear model was
applied to each of the above parameters (excluding T.sub.max), and
the LN-transformed parameters C.sub.max, AUC.sub.(0-24),
AUC.sub.(0-t), and AUC.sub.(0-inf). Initially, the analysis of
variance (ANOVA) model included the following factors: treatment,
sequence, subject within sequence, period, and carryover effect. If
carryover effect was not significant, it was dropped from the
model. The sequence effect was tested using the subject within
sequence mean square, and all other main effects were tested using
the residual error (error mean square).
[0089] Plasma oxymorphone concentrations were listed by subject at
each collection time and summarized using descriptive statistics.
Pharmacokinetic parameters were also listed by subject and
summarized using descriptive statistics.
[0090] Study 1--Two Controlled Release Formulations; Fasted
Patients
[0091] Healthy volunteers received a single oral dose of 20 mg CR
oxymorphone taken with 240 ml water after a 10-hour fast. Subjects
received the tablets of Example 2 (Treatment 1A) or Example 3
(Treatment 1B). Further subjects were given a single oral dose of
10 mg/10 ml oxymorphone solution in 180 ml apple juice followed
with 60 ml water (Treatment 1 C). The orally dosed solution was
used to simulate an immediate release (IR) dose.
[0092] This study had a single-center, open-label, randomized,
three-way crossover design using fifteen subjects. Subjects were in
a fasted state following a 10-hour overnight fast. There was a
14-day washout interval between the three dose administrations. The
subjects were confined to the clinic during each study period.
Subjects receiving Treatment 1C were confined for 18 hours and
subjects receiving Treatments 1A or 1B were confined for 48 hours
after dosing. Ten-milliliter blood samples were collected during
each study period at the 0 hour (predose), and at 0.5, 1, 1.5, 2,
3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, and 48
hours postdose for subjects receiving Treatment 1A or 1B and 0,
0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 10,
12, 14, 16, and 18 hours post-dose. The mean plasma concentration
of oxymorphone versus time for each treatment across all subjects
is shown in table 5.
TABLE-US-00005 TABLE 5 Mean Plasma Concentration vs. Time (ng/ml)
Time (hr) Treatment 1A Treatment 1B Treatment 1C 0 0.000 0.000
0.0000 0.25 0.9489 0.5 0.2941 0.4104 1.3016 0.75 1.3264 1 0.5016
0.7334 1.3046 1.25 1.2041 1.5 0.5951 0.8192 1.0813 1.75 0.9502 2
0.6328 0.7689 0.9055 2.5 0.7161 3 0.5743 0.7341 0.6689 4 0.5709
0.6647 0.4879 5 0.7656 0.9089 0.4184 6 0.7149 0.7782 0.3658 7
0.6334 0.6748 0.3464 8 0.5716 0.5890 0.2610 10 0.4834 0.5144 0.2028
12 0.7333 0.6801 0.2936 14 0.6271 0.6089 0.2083 16 0.4986 0.4567
0.1661 18 0.4008 0.3674 0.1368 20 0.3405 0.2970 24 0.2736 0.2270 28
0.3209 0.2805 32 0.2846 0.2272 36 0.2583 0.1903 48 0.0975
0.0792
[0093] The results are shown graphically in FIG. 5. In both Table 5
and FIG. 5, the results are normalized to a 20 mg dosage. The
immediate release liquid of Treatment 1C shows a classical curve,
with a high and relatively narrow peak, followed by an exponential
drop in plasma concentration. However, the controlled release
oxymorphone tablets exhibit triple peaks in blood plasma
concentration. The first peak occurs (on average) at around 3
hours. The second peak of the mean blood plasma concentration is
higher than the first, occurring around 6-7 hours, on average).
[0094] Occasionally, in an individual, the first peak is higher
than the second, although generally this is not the case. This
makes it difficult to determine the time to maximum blood plasma
concentration (T.sub.max) because if the first peak is higher than
the second, maximum blood plasma concentration (C.sub.max) occurs
much earlier (at around 3 hours) than in the usual case where the
second peak is highest. Therefore, when we refer to the time to
peak plasma concentration (T.sub.max) unless otherwise specified,
we refer to the time to the second peak. Further, when reference is
made to the second peak, we refer to the time or blood plasma
concentration at the point where the blood plasma concentration
begins to drop the second time. Generally, where the first peak is
higher than the second, the difference in the maximum blood plasma
concentration at the two peaks is small. Therefore, this difference
(if any) was ignored and the reported C.sub.max was the true
maximum blood plasma concentration and not the concentration at the
second peak.
TABLE-US-00006 TABLE 6 Pharmacokinetic Parameters of Plasma
Oxymorphone for Study 1 Treatment 1A Treatment 1B Treatment 1C Mean
SD Mean SD Mean SD C.sub.max 0.8956 0.2983 1.0362 0.3080 2.9622
1.0999 T.sub.max 7.03 4.10 4.89 3.44 0.928 0.398 AUC.sub.(0-t)
17.87 6.140 17.16 6.395 14.24 5.003 AUC.sub.(0-inf) 19.87 6.382
18.96 6.908 16.99 5.830 T.sub.1/2el 10.9 2.68 11.4 2.88 6.96 4.61
Units: C.sub.max in ng/ml, T.sub.max in hours, AUC in ng * hr/ml,
T.sub.1/2el in hours.
[0095] Relative bioavailability determinations are set forth in
Tables 7 and 8. For these calculations, AUC was normalized for all
treatments to a 20 mg dose.
TABLE-US-00007 TABLE 7 Relative Bioavailability (F.sub.rel)
Determination Based on AUC.sub.(0-inf) F.sub.rel (1A vs. 1C)
F.sub.rel (1B vs. 1C) F.sub.rel (1A vs. 1B) 1.193 0.203 1.121 0.211
1.108 0.152
TABLE-US-00008 TABLE 8 Relative Bioavailability Determination Based
on AUC.sub.(0-18) F.sub.rel (1A vs. 1C) F.sub.rel (1B vs. 1C)
F.sub.rel (1A vs. 1B) 0.733 0.098 0.783 0.117 0.944 0.110
[0096] Study 2--Two CR Formulations; Fed Patients
[0097] Healthy volunteers received a single oral dose of 20 mg CR
oxymorphone taken with 240 ml water in a fed state. Subjects
received the tablets of Example 2 (Treatment 2A) or Example 3
(Treatment 2B). Further subjects were given a single oral dose of
10 mg/10 ml oxymorphone solution in 180 ml apple juice followed
with 60 ml water (Treatment 2C). The orally dosed solution was used
to simulate an immediate release (IR) dose.
[0098] This study had a single-center, open-label, randomized,
three-way crossover design using fifteen subjects. The subjects
were in a fed state, after a 10-hour overnight fast followed by a
standardized FDA high-fat breakfast. There was a 14-day washout
interval between the three dose administrations. The subjects were
confined to the clinic during each study period. Subjects receiving
Treatment 2C were confined for 18 hours and subjects receiving
Treatments 2A or 2B were confined for 48 hours after dosing.
Ten-milliliter blood samples were collected during each study
period at the 0 hour (predose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6,
7, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, and 48 hours postdose
for subjects receiving Treatment 2A or 2B and 0, 0.25, 0.5, 0.75,
1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, and
18 hours postdose. The mean plasma concentration of oxymorphone
versus time for each treatment across all subjects is shown in
table 9.
TABLE-US-00009 TABLE 9 Mean Plasma Concentration vs. Time (ng/ml)
Time (hr) Treatment 2A Treatment 2B Treatment 2C 0 0.000 0.000
0.0000 0.25 1.263 0.5 0.396 .0553 1.556 0.75 1.972 1 0.800 1.063
1.796 1.25 1.795 1.5 1.038 1.319 1.637 1.75 1.467 2 1.269 1.414
1.454 2.5 1.331 3 1.328 1.540 1.320 4 1.132 1.378 1.011 5 1.291
1.609 0.731 6 1.033 1.242 0.518 7 0.941 0.955 0.442 8 0.936 0.817
0.372 10 0.669 0.555 0.323 12 0.766 0.592 0.398 14 0.641 0.519
0.284 16 0.547 0.407 0.223 18 0.453 0.320 0.173 20 0.382 0.280 24
0.315 0.254 28 0.352 0.319 32 0.304 0.237 36 0.252 0.207 48 0.104
0.077
[0099] The results are shown graphically in FIG. 6. Again, the
results have been normalized to a 20 mg dosage. As with Study 1,
the immediate release liquid of Treatment 2C shows a classical
curve, with a high and relatively narrow peak, followed by an
exponential drop in plasma concentration, while the controlled
release oxymorphone tablets exhibit triple peaks in blood plasma
concentration. Thus, again when we refer to the time to peak plasma
concentration (T.sub.max) unless otherwise specified, we refer to
the time to the second peak.
TABLE-US-00010 TABLE 10 Pharmacokinetic Parameters of Plasma
Oxymorphone for Study 2 Treatment 2A Treatment 2B Treatment 2C Mean
SD Mean SD Mean SD C.sub.max 1.644 0.365 1.944 0.465 4.134 0.897
T.sub.max 3.07 1.58 2.93 1.64 0.947 0.313 AUC.sub.(0-t) 22.89 5.486
21.34 5.528 21.93 5.044 AUC.sub.(0-inf) 25.28 5.736 23.62 5.202
24.73 6.616 T.sub.1/2el 12.8 3.87 11.0 3.51 5.01 2.02 Units:
C.sub.max in ng/ml, T.sub.max in hours, AUC in ng * hr/ml,
T.sub.1/2el in hours.
[0100] In Table 10, the T.sub.max has a large standard deviation
due to the two comparable peaks in blood plasma concentration.
Relative bioavailability determinations are set forth in Tables 11
and 12.
TABLE-US-00011 TABLE 11 Relative Bioavailability Determination
Based on AUC.sub.(0-inf) F.sub.rel (2A vs. 2C) F.sub.rel (2B vs.
2C) F.sub.rel (2A vs. 2B) 1.052 0.187 0.949 0.154 1.148 0.250
TABLE-US-00012 TABLE 12 Relative Bioavailability Determination
Based on AUC.sub.(0-18) F.sub.rel (2A vs. 2C) F.sub.rel (2B vs. 2C)
F.sub.rel (2A vs. 2B) 0.690 0.105 0.694 0.124 1.012 0.175
[0101] As may be seen from tables 5 and 10 and FIGS. 1 and 2, the
C.sub.max for the CR tablets (treatments 1A, 1B, 2A and 2B) is
considerably lower, and the T max much higher than for the
immediate release oxymorphone. The blood plasma level of
oxymorphone remains high well past the 8 (or even the 12) hour
dosing interval desired for an effective controlled release
tablet.
[0102] Study 3-One Controlled Release Formulation; Fed and Fasted
Patients
[0103] This study had a single-center, open-label, analytically
blinded, randomized, four-way crossover design. Subjects randomized
to Treatment 3A and Treatment 3C, as described below, were in a
fasted state following a 10-hour overnight fast. Subjects
randomized to Treatment 3B and Treatment 3D, as described below,
were in the fed state, having had a high fat meal, completed ten
minutes prior to dosing. There was a 14-day washout interval
between the four dose administrations. The subjects were confined
to the clinic during each study period. Subjects assigned to
receive Treatment 3A and Treatment 3B were discharged from the
clinic on Day 3 following the 48-hour procedures, and subjects
assigned to receive Treatment 3C and Treatment 3D were discharged
from the clinic on Day 2 following the 36-hour procedures. On Day 1
of each study period the subjects received one of four
treatments:
[0104] Treatments 3A and 3B: Oxymorphone controlled release 20 mg
tablets from Example 3. Subjects randomized to Treatment 3A
received a single oral dose of one 20 mg oxymorphone controlled
release tablet taken with 240 ml of water after a 10-hour fasting
period. Subjects randomized to Treatment 3B received a single oral
dose of one 20 mg oxymorphone controlled release tablet taken with
240 ml of water 10 minutes after a standardized high fat meal.
[0105] Treatments 3C and 3D: oxymorphone HCl solution, USP, 1.5
mg/ml 10 ml vials. Subjects randomized to Treatment 3C received a
single oral dose of 10 mg (6.7 ml) oxymorphone solution taken with
240 ml of water after a 10-hour fasting period. Subjects randomized
to Treatment 3D received a single oral dose of 10 mg (6.7 ml)
oxymorphone solution taken with 240 ml of water 10 minutes after a
standardized high-fat meal.
[0106] A total of 28 male subjects were enrolled in the study, and
24 subjects completed the study. The mean age of the subjects was
27 years (range of 19 through 38 years), the mean height of the
subjects was 69.6 inches (range of 64.0 through 75.0 inches), and
the mean weight of the subjects was 169.0 pounds (range 117.0
through 202.0 pounds).
[0107] A total of 28 subjects received at least one treatment. Only
subjects who completed all 4 treatments were included in the
summary statistics and statistical analysis.
[0108] Blood samples (7 ml) were collected during each study period
at the 0 hour (predose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,
12, 14, 16, 20, 24, 30, 36, and 48 hours post-dose (19 samples) for
subjects randomized to Treatment 3A and Treatment 3B. Blood samples
(7 ml) were collected during each study period at the 0 hour
(predose), and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5,
6, 8, 10, 12, 14, 16, 20, and 36 hours post-dose (21 samples) for
subjects randomized to Treatment 3C and Treatment 3D.
[0109] The mean oxymorphone plasma concentration versus time curves
for Treatments 3A, 3B, 3C, and 3D are presented in FIG. 7. The
results have been normalized to a 20 mg dosage. The data is
contained in Table 13. The arithmetic means of the plasma
oxymorphone pharmacokinetic parameters and the statistics for all
Treatments are summarized in Table 1.
TABLE-US-00013 TABLE 13 Mean Plasma Concentration vs. Time (ng/ml)
Treatment Treatment Treatment Treatment Time (hr) 3A 3B 3C 3D 0
0.0084 0.0309 0.0558 0.0000 0.25 0.5074 0.9905 0.5 0.3853 0.3380
0.9634 1.0392 0.75 0.9753 1.3089 1 0.7710 0.7428 0.8777 1.3150 1.25
0.8171 1.2274 1.5 1.7931 1.0558 0.7109 1.1638 1.75 0.6357 1.0428 2
0.7370 1.0591 0.5851 0.9424 3 0.6879 0.9858 0.4991 0.7924 4 0.6491
0.9171 0.3830 0.7277 5 0.9312 1.4633 0.3111 0.6512 6 0.7613 1.0441
0.2650 0.4625 8 0.5259 0.7228 0.2038 0.2895 10 0.4161 0.5934 0.1768
0.2470 12 0.5212 0.5320 0.2275 0.2660 14 0.4527 0.4562 0.2081
0.2093 16 0.3924 0.3712 0.1747 0.1623 20 0.2736 0.3021 0.1246
0.1144 24 0.2966 0.2636 0.1022 0.1065 30 0.3460 0.3231 36 0.2728
0.2456 0.0841 0.0743 48 0.1263 0.1241
TABLE-US-00014 TABLE 14 Pharmacokinetic Parameters of Plasma
Oxymorphone for Study 3 Treatment 3A Treatment 3B Treatment 3C
Treatment 3D Mean SD Mean SD Mean SD Mean SD C.sub.max 1.7895
0.6531 1.1410 0.4537 2.2635 1.0008 2.2635 1.0008 T.sub.max 5.65
9.39 5.57 7.14 0.978 1.14 0.978 1.14 AUC.sub.(o-t) 14.27 4.976
11.64 3.869 12.39 4.116 12.39 4.116 AUC.sub.(o-inf) 19.89 6.408
17.71 8.471 14.53 4.909 14.53 4.909 T.sub.1/2el 21.29 6.559 19.29
5.028 18.70 6.618 18.70 6.618 12.0 3.64 12.3 3.99 16.2 11.4 16.2
11.4
[0110] The relative bioavailability calculations are summarized in
tables 15 and 16.
TABLE-US-00015 TABLE 15 Relative Bioavailability Determination
Based on AUC.sub.(0-inf) F.sub.rel F.sub.rel F.sub.rel (3A vs. 3C)
F.sub.rel (3B vs. 3D) (3D vs. 3C) (3A vs. 3B) 1.040 0.1874 0.8863
0.2569 1.368 1.169 0.4328 0.2041
TABLE-US-00016 TABLE 16 Relative bioavailability Determination
Based on AUC.sub.(0-24) F.sub.rel (3A vs. 2C) F.sub.rel (3B vs. 3D)
F.sub.rel (3D vs. 3C) F.sub.rel (3A vs. 3B) 0.9598 0.2151 0.8344
0.100 1.470 0.3922 1.299 0.4638
[0111] The objectives of this study were to assess the relative
bioavailability of oxymorphone from oxymorphone controlled release
(20 mg) compared to oxymorphone oral solution (10 mg) under both
fasted and fed conditions, and to determine the effect of food on
the bioavailability of oxymorphone from the controlled release
formulation, oxymorphone CR, and from the oral solution.
[0112] The presence of a high fat meal had a substantial effect on
the oxymorphone C.sub.max, but less of an effect on oxymorphone AUC
from oxymorphone controlled release tablets. Least Squares (LS)
mean C.sub.max was 58% higher and LS mean AUC.sub.(0-t) and
AUC.sub.(0-inf) were 18% higher for the fed condition (Treatment B)
compared to the fasted condition (Treatment A) based on
LN-transformed data. This was consistent with the relative
bioavailability determination from AUC.sub.(0-inf) since mean
F.sub.rel was 1.17. Mean T.sub.max values were similar
(approximately 5.6 hours), and no significant difference in
T.sub.max was shown using nonparametric analysis. Half value
durations were significantly different between the two
treatments.
[0113] The effect of food on oxymorphone bioavailability from the
oral solution was more pronounced, particularly in terms of AUC. LS
mean C.sub.max was 50% higher and LS mean AUC.sub.(0-t) and
AUC.sub.(0-inf) were 32-34% higher for the fed condition (Treatment
D) compared to the fasted condition (Treatment C) based on
LN-transformed data. This was consistent with the relative
bioavailability determination from AUC.sub.(0-inf) since mean
F.sub.rel was 1.37. Mean T.sub.max (approximately 1 hour) was
similar for the two treatments and no significant difference was
shown.
[0114] Under fasted conditions, oxymorphone controlled release 20
mg tablets exhibited similar extent of oxymorphone availability
compared to 10 mg oxymorphone oral solution normalized to a 20 mg
dose (Treatment A versus Treatment C). From LN-transformed data, LS
mean AUC.sub.(0-t) was 17% higher for oxymorphone CR, whereas LS
mean AUC.sub.(0-inf) values were nearly equal (mean ratio=99%).
Mean F.sub.rel values calculated from AUC.sub.(0-inf) and
AUC.sub.(0-24), (1.0 and 0.96, respectively) also showed similar
extent of oxymorphone availability between the two treatments.
[0115] As expected, there were differences in parameters reflecting
rate of absorption. LS mean C.sub.max was 49% lower for oxymorphone
controlled release tablets compared to the dose-normalized oral
solution, based on LN-transformed data. Half-value duration was
significantly longer for the controlled release formulation (means,
12 hours versus 2.5 hours).
[0116] Under fed conditions, oxymorphone availability from
oxymorphone controlled release 20 mg was similar compared to 10 mg
oxymorphone oral solution normalized to a 20 mg dose (Treatment B
versus Treatment D). From LN-transformed data, LS mean
AUC.sub.(0-inf) was 12% lower for oxymorphone CR. Mean F.sub.rel
values calculated from AUC.sub.(0-inf) and AUC.sub.(0-24), (0.89
and 0.83 respectively) also showed similar extent of oxymorphone
availability from the tablet. As expected, there were differences
in parameters reflecting rate of absorption. LS mean C.sub.max was
46% lower for oxymorphone controlled release tablets compared to
the dose-normalized oral solution, based on LN-transformed data.
Mean T.sub.max was 5.7 hours for the tablet compared to 1.1 hours
for the oral solution. Half-value duration was significantly longer
for the controlled release formulation (means, 7.8 hours versus 3.1
hours).
[0117] The presence of a high fat meal did not appear to
substantially affect the availability following administration of
oxymorphone controlled release tablets. LS mean ratios were 97% for
AUC.sub.(0-t) and 91% for C.sub.max (Treatment B versus A), based
on LN-transformed data. This was consistent with the relative
bioavailability determination from AUC.sub.(0-24), since mean
F.sub.rel was 0.97. Mean T.sub.max was later for the fed treatment
compared to the fasted treatment (5.2 and 3.6 hours, respectively),
and difference was significant.
[0118] Under fasted conditions, oxymorphone controlled release 20
mg tablets exhibited similar availability compared to 10 mg
oxymorphone oral solution normalized to a 20 mg dose (Treatment A
versus Treatment C). From LN-transformed data, LS mean ratio for
AUC.sub.(0-t) was 104.5%. Mean F.sub.rel (0.83) calculated from
AUC.sub.(0-24) also showed similar extent of oxymorphone
availability between the two treatments. Mean T.sub.max was 3.6
hours for the tablet compared to 0.88 for the oral solution.
Half-value duration was significantly longer for the controlled
release formulation (means, 11 hours versus 2.2 hours).
[0119] Under fed conditions, availability from oxymorphone
controlled release 20 mg was similar compared to 10 mg oxymorphone
oral solution normalized to a 20 mg dose (Treatment B versus
Treatment D). From LN-transformed data, LS mean AUC.sub.(0-t) was
14% higher for oxymorphone CR. Mean F.sub.rel (0.87) calculated
from AUC.sub.(0-24) also indicated similar extent of availability
between the treatments. Mean T.sub.max was 5.2 hours for the tablet
compared to 1.3 hour for the oral solution. Half-value duration was
significantly longer for the controlled release formulation (means,
14 hours versus 3.9 hours).
[0120] The extent of oxymorphone availability from oxymorphone
controlled release 20 mg tablets was similar under fed and fasted
conditions since there was less than a 20% difference in LS mean
AUC.sub.(0-t) and AUC.sub.(0-inf) values for each treatment, based
on LN-transformed data. T.sub.max was unaffected by food; however,
LS mean C.sub.max was increased 58% in the presence of the high fat
meal. Both rate and extent of oxymorphone absorption from the
oxymorphone oral solution were affected by food since LS mean
C.sub.max and AUC values were increased approximately 50 and 30%,
respectively. T.sub.max was unaffected by food. Under both fed and
fasted conditions, oxymorphone controlled release tablets exhibited
similar extent of oxymorphone availability compared to oxymorphone
oral solution since there was less than a 20% difference in LS mean
AUC(0-t) and AUC(0-inf) values for each treatment.
[0121] Bioavailability following oxymorphone controlled release 20
mg tablets was also similar under fed and fasted conditions since
there was less than a 20% difference in LS mean C.sub.max and AUC
values for each treatment. T.sub.max was later for the fed
condition. The presence of food did not affect the extent of
availability from oxymorphone oral solution since LS mean AUC
values were less than 20% different. However, C.sub.max was
decreased 35% in the presence of food. T.sub.max was unaffected by
food. Under both fed and fasted conditions, oxymorphone controlled
release tablets exhibited similar extent of availability compared
to oxymorphone oral solution since there was less than a 20%
difference in LS mean AUC values for each treatment.
[0122] The mean 6-OH oxymorphone plasma concentration versus time
curves for Treatments 3A, 3B, 3C, and 3D are presented in FIG. 8.
The data is contained in Table 17.
TABLE-US-00017 TABLE 17 Mean Plasma Concentration vs. Time (ng/ml)
6-Hydroxyoxymorphone Treatment Treatment Treatment Treatment Time
(hr) 3A 3B 3C 3D 0 0.0069 0.0125 0.0741 0.0000 0.25 0.7258 0.4918
0.5 0.5080 0.1879 1.2933 0.5972 0.75 1.3217 0.7877 1 1.0233 0.4830
1.1072 0.8080 1.25 1.0069 0.7266 1.5 1.1062 0.7456 0.8494 0.7001
1.75 0.7511 0.6472 2 1.0351 0.7898 0.6554 0.5758 3 0.9143 0.7619
0.6196 0.5319 4 0.8522 0.7607 0.4822 0.5013 5 0.8848 0.8548 0.3875
0.4448 6 0.7101 0.7006 0.3160 0.3451 8 0.5421 0.5681 0.2525 0.2616
10 0.4770 0.5262 0.2361 0.2600 12 0.4509 0.4454 0.2329 0.2431 14
0.4190 0.4399 0.2411 0.2113 16 0.4321 0.4230 0.2385 0.2086 20
0.3956 0.4240 0.2234 0.1984 24 0.4526 0.4482 0.2210 0.2135 30
0.4499 0.4708 36 0.3587 0.3697 0.1834 0.1672 48 0.3023 0.3279
TABLE-US-00018 TABLE 18 Pharmacokinetic Parameters of Plasma
Oxymorphone for Study 3 Treatment 3A Treatment 3B Treatment 3C
Treatment 3D Mean SD Mean SD Mean SD Mean SD C.sub.max 1.2687
0.5792 1.1559 0.4848 1.5139 0.7616 0.9748 0.5160 T.sub.max 3.61
7.17 5.20 9.52 0.880 0.738 1.30 1.04 AUC.sub.(o-t) 22.47 10.16
22.01 10.77 10.52 4.117 9.550 4.281 AUC.sub.(o-inf) 38.39 23.02
42.37 31.57 20.50 7.988 23.84 11.37 T.sub.1/2el 39.1 36.9 39.8 32.6
29.3 12.0 44.0 35.00
[0123] Study 4-Controlled Release 20 mg vs Immediate Release 10
mg
[0124] A study was conducted to compare the bioavailability and
pharmacokinetics of controlled release and immediate release
oxymorphone tablets under single-dose and multiple-dose (steady
state) conditions. For the controlled release study, healthy
volunteers received a single dose of a 20 mg controlled release
oxymorphone table on the morning of Day 1. Beginning on the morning
of Day 3, the volunteers were administered a 20 mg controlled
release oxymorphone tablet every 12 hours through the morning dose
of Day 9. For the immediate release study, healthy volunteers
received a single 10 mg dose of an immediate release oxymorphone
tablet on the morning of Day 1. On the morning of Day 3, additional
10 mg immediate release tablets were administered every six hours
through the first two doses on Day 9.
[0125] FIG. 9 shows the average plasma concentrations of
oxymorphone and 6-6-hydroxy oxymorphone for all subjects after a
single dose either controlled release (CR) 20 mg or immediate
release (IR) 10 mg oxymorphone. The data in the figure (as with the
other relative experimental data herein) is normalized to a 20 mg
dose. The immediate release tablet shows a classical curve, with a
high, relatively narrow peak followed by an exponential drop in
plasma concentration. The controlled release oxymorphone tablets
show a lower peak with extended moderate levels of oxymorphone and
6-hydroxy oxymorphone. Table 19 shows the levels of oxymorphone and
6-hydroxy oxymorphone from FIG. 9 in tabular form.
TABLE-US-00019 TABLE 19 Mean Plasma Concentration (ng/ml) 6-
Oxymorphone Hydroxyoxymorphone Controlled Immediate Controlled
Immediate Release Release Release Release Hour 20 mg 10 mg 20 mg 10
mg 0.00 0.00 0.00 0.00 0.00 0.25 0.22 1.08 0.14 0.73 0.50 0.59 1.69
0.45 1.22 1.00 0.77 1.19 0.53 0.79 1.50 0.84 0.91 0.53 0.57 2.00
0.87 0.75 0.60 0.47 3.00 0.83 0.52 0.55 0.34 4.00 0.73 0.37 0.53
0.27 5.00 0.94 0.36 0.46 0.23 6.00 0.81 0.28 0.41 0.18 8.00 0.73
0.20 0.37 0.14 10.0 0.60 0.19 0.35 0.15 12.0 0.67 0.25 0.32 0.13
16.0 0.39 0.16 0.29 0.13 24.0 0.23 0.07 0.29 0.13 30.0 0.12 0.01
0.17 0.04 36.0 0.05 0.00 0.11 0.00 48.0 0.00 0.00 0.07 0.01
[0126] FIG. 10 shows the average plasma concentrations of
oxymorphone and 6-hydroxyoxymorphone for all subjects in the steady
state test, for doses of controlled release 20 mg tablets and
immediate release 10 mg tablets of oxymorphone. The figure shows
the plasma concentrations after the final controlled release tablet
is given on Day 9, and the final immediate release tablet is given
12 hours thereafter. The steady state administration of the
controlled release tablets clearly shows a steady moderate level of
oxymorphone ranging from just over 1 ng/ml to almost 1.75 ng/ml
over the course of a twelve hour period, where the immediate
release tablet shows wide variations in blood plasma concentration.
Table 20 shows the levels of oxymorphone and 6-hydroxyoxymorphone
from FIG. 10 in tabular form.
TABLE-US-00020 TABLE 20 Summary of Mean Plasma Concentration
(ng/ml) Oxymorphone 6-Hydroxyoxymorphone Controlled Immediate
Controlled Immediate Release Release Release Release Day Hour 20 mg
10 mg 20 mg 10 mg 4 0.00 1.10 0.75 0.89 0.72 5 0.00 1.12 0.84 1.15
0.88 6 0.00 1.20 0.92 1.15 0.87 7 0.00 1.19 0.91 1.27 1.00 8 0.00
1.19 0.86 1.29 0.98 9 0.00 1.03 1.07 1.09 1.05 0.25 2.64 1.70 0.50
3.12 1.50 2.09 1.00 2.47 1.70 1.68 1.50 2.05 1.63 1.55 2.00 1.78
1.64 1.30 3.00 1.27 1.47 1.11 4.00 0.98 1.39 0.98 5.00 1.01 1.21
0.89 6.00 0.90 1.06 0.84 6.25 1.17 0.88 6.50 1.88 1.06 7.00 2.12
1.20 7.50 2.24 1.15 8.00 1.32 2.01 0.97 1.03 9.00 1.52 0.90 10.0
1.32 1.24 0.85 0.84 11.0 1.11 0.74 12.0 1.18 0.96 0.79 0.70
TABLE-US-00021 TABLE 21 Mean Single-Dose Pharmacokinetic Results
Controlled Immediate Release 20 mg Release 10 mg oxymor- 6-OH-
6-OH-oxy- phone oxymorphone oxymorphone morphone AUC.sub.(o-t)
14.74 11.54 7.10 5.66 AUC.sub.(o-inf) 15.33 16.40 7.73 8.45
C.sub.max(ng/ml) 1.12 0.68 1.98 1.40 T.sub.max(hr) 5.00 2.00 0.50
0.50 T1/2(hr) 9.25 26.09 10.29 29.48
[0127] Parent 6-OH oxymorphone AUC.sub.(0-t) values were lower than
the parent compound after administration of either dosage form, but
the AUC.sub.(o-inf) values are slightly higher due to the longer
half-life for the metabolite. This relationship was similar for
both the immediate-release (IR) and controlled release (CR) dosage
forms. As represented by the average plasma concentration graph,
the CR dosage form has a significantly longer time to peak
oxymorphone concentration and a lower peak oxymorphone
concentration. The 6-OH oxymorphone peak occurred sooner than the
parent peak following the CR dosage form, and simultaneously with
the parent peak following the IR dosage form.
[0128] It is important to note that while the present invention is
described and exemplified using 20 mg tablets, the invention may
also be used with other strengths of tablets. In each strength, it
is important to note how a 20 mg tablet of the same composition
(except for the change in strength) would act. The blood plasma
levels and pain intensity information are provided for 20 mg
tablets, however the present invention is also intended to
encompass 5 to 80 mg controlled release tablets. For this reason,
the blood plasma level of oxymorphone or 6-hydroxyoxymorphone in
nanograms per milliliter of blood, per mg oxymorphone (ng/mgml)
administered is measured. Thus at 0.02 ng/mgml, a 5 mg tablet
should produce a minimum blood plasma concentration of 0.1 ng/ml. A
stronger tablet will produce a higher blood plasma concentration of
active molecule, generally proportionally. Upon administration of a
higher dose tablet, for example 80 mg, the blood plasma level of
oxymorphone and 6-OH oxymorphone may more than quadruple compared
to a 20 mg dose, although conventional treatment of low
bioavailability substances would lead away from this conclusion. If
this is the case, it may be because the body can only process a
limited amount oxymorphone at one time. Once the bolus is
processed, the blood level of oxymorphone returns to a proportional
level.
[0129] It is the knowledge that controlled release oxymorphone
tablets are possible to produce and effective to use, which is most
important, made possible with the high bioavailability of
oxymorphone in a controlled release tablet. This also holds true
for continuous periodic administration of controlled release
formulations. The intent of a controlled release opioid formulation
is the long-term management of pain. Therefore, the performance of
a composition when administered periodically (one to three times
per day) over several days is important. In such a regime, the
patient reaches a "steady state" where continued administration
will produce the same results, when measured by duration of pain
relief and blood plasma levels of pharmaceutical. Such a test is
referred to as a "steady state" test and may require periodic
administration over an extended time period ranging from several
days to a week or more. Of course, since a patient reaches steady
state in such a test, continuing the test for a longer time period
should not affect the results. Further, when testing blood plasma
levels in such a test, if the time period for testing exceeds the
interval between doses, it is important the regimen be stopped
after the test is begun so that observations of change in blood
level and pain relief may be made without a further dose affecting
these parameters.
[0130] Study 5--Controlled Release 40 mg vs Immediate Release
4.times.10 mg under Fed and Fasting Conditions
[0131] The objectives of this study were to assess the relative
bioavailability of oxymorphone from oxymorphone controlled release
(40 mg) compared to oxymorphone immediate release (4.times.10 mg)
under both fasted and fed conditions, and to determine the effect
of food on the bioavailability of oxymorphone from the controlled
release formulation, oxymorphone CR, and from the immediate release
formulation, oxymorphone IR.
[0132] This study had a single-center, open-label, analytically
blinded, randomized, four-way crossover design. Subjects randomized
to Treatment 5A and Treatment 5C, as described below, were in a
fasted state following a 10-hour overnight fast. Subjects
randomized to Treatment 5B and Treatment 5D, as described below,
were in the fed state, having had a high fat meal, completed ten
minutes prior to dosing. There was a 14-day washout interval
between the four dose administrations. The subjects were confined
to the clinic during each study period. Subject assigned to receive
Treatment 5A and Treatment 5B were discharged from the clinic on
Day 3 following the 48-hour procedures, and subjects assigned to
receive Treatment 5C and Treatment 5D were discharged from the
clinic on Day 2 following the 36-hour procedures. On Day 1 of each
study period the subjects received one of four treatments:
[0133] Treatments 5A and 5B: Oxymorphone controlled release 40 mg
tablets from Table 2. Subjects randomized to Treatment 5A received
a single oral dose of one 40 mg oxymorphone controlled release
tablet taken with 240 ml of water after a 10-hour fasting period.
Subjects randomized to Treatment 5B received a single oral dose of
one 40 mg oxymorphone controlled release tablet taken with 240 ml
of water 10 minutes after a standardized high fat meal.
[0134] Treatments 5C and 5D: Immediate release tablet
(IR)4.times.10 mg Oxymorphone. Subjects randomized to Treatment 5C
received a single oral dose of 4.times.10 mg oxymorphone IR tablet
taken with 240 ml of water after a 10-hour fasting period. Subjects
randomized to Treatment 5D received a single oral dose of
4.times.10 mg oxymorphone IR tablet taken with 240 ml of water 10
minutes after a standardized high-fat meal.
[0135] A total of 28 male subjects were enrolled in the study, and
25 subjects completed the study. A total of 28 subjects received at
least one treatment. Only subjects who completed all 4 treatments
were included in the summary statistics and statistical
analysis.
[0136] Blood samples (7 ml) were collected during each study period
at the 0 hour (predose), and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4,
5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post-dose (19
samples) for subjects randomized to all Treatments.
[0137] The mean oxymorphone plasma concentration versus time curves
for Treatments 5A, 5B, 5C, and 5D are presented in FIG. 11. The
data is contained in Table 22. The arithmetic means of the plasma
oxymorphone pharmacokinetic parameters and the statistics for all
Treatments are summarized in Table 23.
TABLE-US-00022 TABLE 22 Mean Plasma Concentration vs. Time (ng/ml)
Treatment Treatment Treatment Treatment Time (hr) 5A 5B 5C 5D 0
0.00 0.00 0.00 0.00 0.25 0.47 0.22 3.34 1.79 0.50 1.68 0.97 7.28
6.59 0.75 1.92 1.90 6.60 9.49 1 2.09 2.61 6.03 9.91 1.5 2.18 3.48
4.67 8.76 2 2.18 3.65 3.68 7.29 3 2.00 2.86 2.34 4.93 4 1.78 2.45
1.65 3.11 5 1.86 2.37 1.48 2.19 6 1.67 2.02 1.28 1.71 8 1.25 1.46
0.92 1.28 10 1.11 1.17 0.78 1.09 12 1.34 1.21 1.04 1.24 24 0.55
0.47 0.40 0.44 36 0.21 0.20 0.16 0.18 48 0.06 0.05 0.04 0.05 60
0.03 0.01 0.01 0.01 72 0.00 0.00 0.00 0.00
TABLE-US-00023 TABLE 23 Pharmacokinetic Parameters of Plasma
Oxymorphone for Study 5 Treatment Treatment Treatment Treatment 5A
5B 5C 5D Mean SD Mean SD Mean SD Mean SD C.sub.max 2.79 0.84 4.25
1.21 9.07 4.09 12.09 5.42 T.sub.max 2.26 2.52 1.96 1.06 0.69 0.43
1.19 0.62 AUC.sub.(o-t) 35.70 10.58 38.20 11.04 36.00 12.52 51.35
20.20 AUC.sub.(o-inf) 40.62 11.38 41.17 10.46 39.04 12.44 54.10
20.26 T.sub.1/2el 12.17 7.57 10.46 5.45 11.65 6.18 9.58 3.63
[0138] The relative bioavailability calculations are summarized in
Tables 24 and 25.
TABLE-US-00024 TABLE 24 Relative Bioavailability Determination
Based on AUC.sub.(o-inf) F.sub.rel (5D vs. 5C) F.sub.rel (5B vs.
5A) 1.3775 1.0220
TABLE-US-00025 TABLE 25 Relative bioavailability Determination
Based on AUC.sub.(o-24) F.sub.rel (5D vs. 5C) F.sub.rel (5B vs. 5A)
1.4681 1.0989
[0139] The mean 6-OH oxymorphone plasma concentration versus time
curves for Treatments 5A, 5B, 5C, and 5D are presented in FIG. 12.
The data is contained in Table 26.
TABLE-US-00026 TABLE 26 Mean Plasma Concentration vs. Time (ng/ml)
6-Hydroxyoxmorphone Treatment Treatment Treatment Treatment Time
(hr) 5A 5B 5C 5D 0 0.00 0.00 0.00 0.00 0.25 0.27 0.05 2.36 0.50
0.05 1.32 0.31 5.35 1.98 0.75 1.37 0.59 4.53 2.97 1 1.44 0.82 3.81
2.87 1.5 1.46 1.09 2.93 2.58 2 1.46 1.28 2.37 2.29 3 1.39 1.14 1.69
1.72 4 1.25 1.14 1.33 1.26 5 1.02 1.00 1.14 1.01 6 0.93 0.86 0.94
0.86 8 0.69 0.72 0.73 0.77 10 0.68 0.67 0.66 0.75 12 0.74 0.66 0.70
0.77 24 0.55 0.52 0.54 0.61 36 0.23 0.30 0.28 0.27 48 0.18 0.20
0.20 0.19 60 0.09 0.10 0.09 0.09 72 0.06 0.06 0.04 0.05
TABLE-US-00027 TABLE 27 Pharmacokinetic Parameters of Plasma
6-Hydroxyoxymorphone for Study 5 Treatment Treatment Treatment
Treatment 5A 5B 5C 5D Mean SD Mean SD Mean SD Mean SD C.sub.max
1.88 0.69 1.59 0.63 6.41 3.61 3.79 1.49 T.sub.max 1.48 1.18 2.73
1.27 0.73 1.47 1.18 0.74 AUC.sub.(o-t) 28.22 10.81 26.95 11.39
33.75 10.29 32.63 13.32 AUC.sub.(o-inf) 33.15 11.25 32.98 10.68
37.63 17.01 36.54 13.79 T.sub.1/2el 17.08 7.45 21.92 8.41 16.01
6.68 16.21 7.42
Example 5
[0140] Introduction
[0141] Oxymorphone HCl is highly metabolized principally in the
liver and undergoes conjugation with glucuronic acid to form both
active and inactive products. Cone et al. reported on the urinary
metabolites of oxymorphone following administration of a 10 mg oral
dose in 10 healthy subjects. The concentrations of oxymorphone and
6-OH-oxymorphone were measured before and after hydrolysis of the
urine. On average, 49% of the administered dose was recovered in
the urine over a 120-hour collection interval. The majority of the
recovery (.about.42% of the dose, 82% of the amount recovered)
occurred in the first 24 hours. Very little unchanged oxymorphone
was recovered in the urine (1.9%, range 0.3% to 0.5%). Conjugated
oxymorphone accounted for an average of 44.1% (range 27.2% to
63.1%) of the administered dose. Urinary recovery of the 6-OH
metabolite accounted for approximately 3% of the dose (.about.0.3%
free and 2.6% conjugated). The identity, with respect to type
(e.g., glucuronic acid) or position (e.g., 3- to 14-), of the
oxymorphone conjugates was not identified. None of the animal
species (rat, dog, guinea pig, or rabbit) had a urinary metabolite
profile that was similar to man.
[0142] Study Objectives
[0143] The objective of this study is to determine the
pharmacokinetics and metabolism of EN3202 (oxymorphone
hydrochloride extended-release) tablets in patients with hepatic
impairment under fasting conditions.
[0144] Methods
[0145] Clinical Study Design and Conduct
[0146] This study employed a single-dose, parallel group design in
12 subjects with chronic hepatic cirrhosis (6 in Child-Pugh Class A
and 6 in Child-Pugh Class B or worse) and 12 healthy controls
matched for age, weight, and gender. Each subject received a single
20 mg dose of ER oxymorphone. The oxymorphone ER tablets
administered were according to the now-available commercial formula
of Opana.RTM. 20 mg strength, which also contains the inactive
ingredients hypromellose, iron oxide black, methylparaben,
propylene glycol, silicified microcrystalline cellulose, sodium
stearyl fumarate, TIMERx.RTM.-N, titanium dioxide and triacetin,
FD&C blue No. 1, FD&C yellow No. 6, and FD&C yellow No.
10. Naltrexone 50 mg was administered on the evening prior to
administration of the ER oxymorphone dose. Plasma and urine samples
were collected at specified intervals for six days after the dose
to determine oxymorphone and metabolite concentrations. Study
participants were housed in the clinical research facility
throughout the treatment period, beginning on the evening prior to
administration of the test medication and extending until
collection of the 120-hour blood sample and urine samples. While in
the clinic, the subjects were to refrain from strenuous physical
activity.
[0147] Overall Study Design
[0148] The study procedures are outlined in the following table
(Table 28).
TABLE-US-00028 TABLE 28 Schedule of Study Evaluations Phase
Screening VISIT NUMBER Treatment 1 2 Period DAY -14 -1 1 2 3 4 5 6
Medical/Medication History X Informed Consent X Assessment of
Eligibility X X Physical Examination X X 12-Lead Electrocardiogram
X Clinical Laboratory Tests X X Vital Signs X X X X X X X X Body
Weight X X Urine Drug Screen X X Naltrexone Dose X ER oxymorphone
Dose X Plasma Samples (a) (a) (a) (a) (a) (a) Urine Collection (b)
(b) (b) (b) (b) (b) Assessment of Adverse Events X X X X X X (a)
Plasma sample times: 0 (pre-dose), 0.5, 1.0, 1.5, 2.0, 3.0, 4.0,
5.0, 6.0, 8.0, 10.0, 12.0, 18.0, 24, 30, 36, 48, 60, 72, 84, 96,
108, and 120 hours after dose administration. (b) Urine collection
intervals: 0 (pre-dose), 0-12, 12-24, 24-48, 48-72, 72-96, and
96-120 hours after administration of the test medication.
[0149] A series of screening evaluations were performed in order to
determine whether prospective study participants met the selection
criteria for the trial. Screening evaluations were performed within
a 14-day period, prior to receiving the study medication. Screening
evaluations consisted of a medical history, a review of systems,
medication history, physical examination, vital signs, weight,
12-lead electrocardiogram (ECG), laboratory evaluations (standard
hematology and serum chemistry panels, and urinalysis), and urine
drug screen. Additional vital signs determination, including pulse,
blood pressure, and respiratory rate were obtained at 24, 48, 72,
96, and 120 hours after administration of the test medication.
Blood pressure and pulse were obtained with the subject in the
sitting position after sitting for 5 minutes. Additional vital
signs obtained during the course of the study, when clinically
indicated, were to be supplied to the sponsor. Laboratory
evaluations, physical examination and vitals signs measurements
were repeated at the conclusion of the treatment period. Screening
tests for hepatitis and HIV infection were obtained at the
Screening visit only.
[0150] Any significant abnormalities were to be fully investigated.
Whenever possible, the etiology of the abnormal findings were
documented on the case report form (CRF). Laboratory results with
significantly abnormal values were to be repeated for verification.
Any significant laboratory abnormalities that were either serious
or unexpected were to be promptly reported to the study monitor.
Any additional relevant laboratory results obtained by the
investigator during the course of the study were to be supplied to
the sponsor.
[0151] During the study period, study participants reported to the
clinic on the evening prior to dose administration and remained in
the clinic until released by the investigator following the final
blood draw on Study Day 6 and the study evaluations to be conducted
at the end of study. Final study evaluations included physical
exam, laboratory evaluations, vital signs, and assessment of
adverse experiences.
[0152] At the screening visit, subjects were informed not to take
any medications (Rx or OTC) until the study began. Hepatically
impaired subjects could take approved prescribed concomitant
medications. The investigator informed each prospective subject of
the nature of the study, explained the potential risks, and
obtained written informed consent from the subject prior to
performing any procedures involving more than minimal risk and
prior to the administration of study medication. Participants had
to meet all of the study entrance criteria to continue in the
study.
[0153] Hepatically impaired subjects of either sex were enrolled in
the two Child-Pugh classes, six in Class A and six in Class B or
worse, as they became available. The 12 healthy volunteers were
matched to hepatically impaired subjects by age, weight, and
gender.
[0154] This was a single-dose trial. As a result, any subject who
received the dose of test medication should have remained in the
trial and completed all required tests and evaluations. Reasons for
premature discontinuation are discussed below. [0155] The subject
withdrew their consent for further participation; [0156] The
investigator determined that continued participation in the trial
placed the subject at unacceptable risk; and [0157] The
investigator determined that the subject required medical treatment
that could not be administered at the study facility.
[0158] Subjects who withdrew from the study prior to completion of
the study evaluations and blood samples scheduled for 72 hours
following dose administration could be replaced. Up to 28
participants could be enrolled to allow for completion of 24
subjects. Plasma samples were not to be analyzed for subjects who
discontinued from the trial prior to collection of the 72-hour
blood sample. If a subject withdrew from the study, the
investigator was to contact the monitor to discuss the necessity of
replacement; the decision was to be made prior to analysis of the
plasma samples. The replacement subject was to match the population
of the subject who was withdrawn (i.e., healthy control or
hepatically impaired).
[0159] The date the subject was withdrawn from the study and the
reason for discontinuation was to be recorded on the CRF. When a
subject was withdrawn from the study (regardless of the reason),
all evaluations required at the final study visit were to be
performed.
[0160] Selection of the Study Population
[0161] Participants were selected from hepatically impaired and
healthy adult volunteers in the general geographic area of the
clinical research facility.
[0162] Twelve healthy volunteers had to meet all of the following
criteria for inclusion into the study: [0163] Healthy males or
nonpregnant females aged 18 to 70 years of age. Female patients of
childbearing potential must have had a negative serum .beta.-hCG
level consistent with nongravid state at the screening visit and
agreed to use an appropriate method of contraception; [0164] Had
body weights not less than 110 lb and were within 30% of the
Metropolitan Life Insurance Company's standards dated 1983 (see
Appendices B and C of the protocol); [0165] Able to communicate
effectively with the study personnel; [0166] Able to match with a
hepatically-impaired volunteer for gender and as closely as
possible with regard to body weight (.+-.15%) and age (.+-.5
years); [0167] No significant disease or abnormal laboratory values
as determined by medical history, physical examination, or
laboratory evaluations, conducted at the Screening visit or on
admission to the clinic; [0168] Had a normal 12-lead ECG, without
any clinically significant abnormalities of rate, rhythm, or
conduction; [0169] Had not consumed alcoholic beverages within 72
hours prior to administration of the first dose of study
medication; and [0170] Was adequately informed of the nature and
risks of the study and gave written informed consent prior to
receiving study medication.
[0171] Twelve male or female subjects with chronic hepatic
cirrhosis had to meet the following criteria for inclusion into the
study: [0172] Male or nonpregnant female 18 to 70 years of age.
Female patients of childbearing potential must have had a negative
serum .beta.-hCG level consistent with nongravid state at the
screening visit and agreed to use an appropriate method of
contraception; [0173] Had a diagnosis of chronic (for more than six
months), stable (no acute episodes of illness within the previous
two months due to deterioration of hepatic function) hepatic
insufficiency with features of cirrhosis due to any etiology;
[0174] Had a total score on the Child-Pugh scale ranging from 5 to
14 at screening. A minimum of six subjects must have had Grade B or
worse hepatic impairment (total score of 7 to 14); [0175] Had body
weights not less than 110 lb and within 30% of the Metropolitan
Life Insurance Company's standards dated 1983 (see Appendices B and
C of the protocol); [0176] Were able to communicate effectively
with study personnel; [0177] Had a prothrombin time<10 seconds
over control; [0178] Had a hemoglobin concentration.gtoreq.10 g/dL;
[0179] Had a platelet count>50,000/.mu.; [0180] Had a normal
12-lead electrocardiogram, without any clinically significant
abnormalities of rate, rhythm, or conduction; [0181] Had not
consumed alcoholic beverages within 72 hours prior to
administration of the first dose of study medication; and [0182]
Were adequately informed of the nature and risks of the study and
gave written informed consent prior to receiving study
medication.
[0183] Healthy participants to whom any of the following applied
were to be excluded from the study: [0184] Known hypersensitivity
or allergy to oxymorphone or naltrexone; [0185] Any disease or
condition (medical or surgical) which might compromise the
hematologic, cardiovascular, pulmonary, renal, gastrointestinal,
hepatic, or central nervous system, or other conditions that may
interfere with the absorption, distribution, metabolism, or
excretion of study drug, or would place the subject at increased
risk; [0186] The presence of abnormal laboratory values which were
considered clinically significant. In addition, no subject with
tests of liver function (SGOT, SGPT) above 1.25 times the upper
limit of normal, total bilirubin above the upper limit of normal,
serum creatinine above the upper limit of normal, or hematologic
function (hemoglobin, hematocrit, white blood cells, or platelets)
below the lower limit of normal were to be admitted to the study;
[0187] Positive screen for Hepatitis B consisting of HBsAg
(Hepatitis B Surface Antigen) or HIV; [0188] Received any
investigational drug within a period of 30 days prior to enrollment
in the study or any prescription drug therapy within 2 weeks of
initiation of the study. This exclusion was extended to 4 weeks for
any drugs known to affect hepatic drug metabolism. No
non-prescription (OTC) drugs could be taken within 24 hours of
admission into the study; [0189] A positive urine drug screen
including alcohol, cocaine, THC, barbiturates, amphetamines,
benzodiazepines, and opiates; [0190] Any history of alcohol abuse,
illicit drug use, significant mental illness, physical dependence
to any opioid, or any history of drug abuse or addiction; [0191] A
history of difficulty with donating blood; or [0192] Received the
study medication previously.
[0193] Hepatically impaired participants to whom any of the
following applied were to be excluded from the study: [0194] Known
hypersensitivity or allergy to oxymorphone or naltrexone; [0195]
Had any disease or condition (medical or surgical) that might
compromise the hematologic, cardiovascular, pulmonary, renal,
gastrointestinal, or central nervous system, other than those
relating to liver disease; [0196] The presence of significant
abnormalities on pre-study screening clinical examination or
laboratory measurements, other than those related to liver disease,
carried out about 2 weeks prior to commencement of the study;
[0197] Was receiving oral contraceptive and/or hormone-replacement
therapy; [0198] Had a positive screen for either Hepatitis B
(Hepatitis B Surface Antigen) or HIV; [0199] Received an
investigational drug within a period of 30 days prior to enrollment
in the study, or used an unacceptable concomitant medication;
[0200] Had a positive urine drug screen including ethanol, cocaine,
THC, barbiturates, amphetamines, benzodiazepines, and opiates;
[0201] Any history of alcohol abuse illicit drug use, had
significant mental illness, physical dependence to any opioid, or
any history of drug abuse or addiction; [0202] Had a history of
difficulty donating blood; or [0203] Had received the study
medication previously.
[0204] Hepatically impaired subjects of either sex were enrolled in
the two Child-Pugh classes, six in Class A and six in Class B or
worse, as they became available. The 12 healthy volunteers were
matched to hepatically impaired subjects by age, weight, and
gender.
[0205] Study Medications
[0206] All study medications were supplied by the sponsor.
Medications utilized in this trial were: [0207] EN3202 (oxymorphone
hydrochloride extended-release) tablets 20 mg; [0208] ReVia.RTM.
(naltrexone hydrochloride) tablets 50 mg. In order to protect the
subjects from potential opioid related adverse events, the opioid
antagonist ReVia.RTM. (naltrexone hydrochloride) was administered
at a dosage of 50 mg once, on the evening prior to administration
of the first oxymorphone dose (Day-1). A single 20 mg dose EN3202
was administered following an overnight fast (from approximately
22:00 on the evening prior to dose administration) at approximately
08:00, and participants were not allowed to eat until at least four
hours after the dose.
[0209] All doses were administered with 240 mL of ambient water.
Participants were instructed to drink all of the water.
[0210] The study was neither blinded nor randomized.
[0211] Safety Assessments
[0212] Although a standard 12-lead ECG was only scheduled at
Screening, additional ECGs were to be obtained if clinically
indicated. A follow-up ECG was to be obtained if any significant
adverse events were detected after dose administration that would
warrant an ECG. Any additional relevant data obtained by the
investigator during the course of the study was to be supplied to
the sponsor.
[0213] Routine vital signs, including pulse, respirations, blood
pressure and temperature were obtained in conjunction with the
physical examination and just prior to administration of the test
medication. Additional vital signs determination, including pulse,
blood pressure, and respiratory rate were obtained at 24, 48, 72,
96, and 120 hours after administration of the test medication.
[0214] Blood pressure and pulse were obtained with the subject in
the sitting position after sitting for 5 minutes. Additional vital
signs obtained during the course of the study, when clinically
indicated, were to be supplied to the sponsor. A battery of
clinical laboratory tests (including hematology, serum chemistry,
and urinalysis) was obtained at screening and on the last day of
the study (Day 6). A physical examination was performed at
screening and on the last day of the study (Day 6).
[0215] Each subject was carefully monitored for the development of
any adverse experiences. This information was obtained in the form
of non-leading questions (e.g., "How are you feeling?") and from
signs and symptoms detected during each examination, observations
of the study personnel or spontaneous reports from the
subjects.
[0216] Analytical Methods
[0217] A total of five (5) validated LC/MS/MS methods were utilized
to measure the concentrations of oxymorphone, 6-OH-oxymorphone, and
oxymorphone-3-glucuronide in plasma and urine samples. The methods
include: oxymorphone and 6-OH-oxymorphone in plasma (M001005.01);
oxymorphone-3-glucuronide in plasma (M001107.00);
oxymorphone-3-glucuronide in urine (M001106.00); oxymorphone and
6-OH-oxymorphone in urine (M001007.00); and "Total" oxymorphone and
6-OH-oxymorphone in urine (M001001.00). In all methods, the
internal standards are d3-oxymorphone, d3-6-OH-oxymorphone, and
d3-oxymorphone-3-glucuronide for oxymorphone, 6-OH-oxymorphone, and
oxymorphone-3-glucuronide, respectively. The methods for
simultaneous determination of oxymorphone and 6-OH-oxymorphone
utilize liquid-liquid extraction of plasma or urine; the method for
oxymorphone-3-glucuronide utilizes solid phase extraction. The
method for "Total" oxymorphone and 6-OH-oxymorphone includes
incubation of the urine sample with .beta.-glucuronidase for two
hours at 50.degree. C. prior to addition of the internal standard
and extraction. Validation results are summarized in the following
tables:
TABLE-US-00029 TABLE 29 Summary of Method Validation Results for
Plasma Analytes Parameter OXM 6-OH-OXM OXM-3-G Standard
Concentrations (ng/mL) 0.1, 0.2, 0.5, 1, 5, 10, 0.1, 0.2, 0.5, 1,
5, 10, 5, 12.5, 25, 50, 125, 18, 20 18, 20 200, 250 QC
Concentrations (ng/mL) 0.3, 6, 14 0.3, 6, 14 15, 75, 180 Linearity
(mean r) 0.9994 0.9987 0.9982 Linear Range (ng/mL) 0.1-20 0.1-20
5-250 LOQ (ng/mL) 0.1 0.1 5.0 Intra-day Precision (% CV)* 1.43-3.93
2.12-7.87 1-39-6.79 Intra-day Accuracy (% Actual)* 94.33-96.56
98.17-102.56 101.00-105.31 Inter-day Precision (% CV)* 2.86-7.77
3.83-7.74 3.85-5.53 Inter-day Accuracy (% Actual)* 97.31-99.36
100.36-101.70 98.99-102.36 Recovery (%) 53.98 22.96 79.30
*precision and accuracy results based on QC samples OXM =
oxymorphone 6-OH-OXM = 6-OH-oxymorphone OXM-3-G =
oxymorphone-3-glucuronide
TABLE-US-00030 TABLE 30 Summary of Method Validation Results for
Urine Analytes Parameter OXM 6-OH-OXM OXM-3-G Standard
Concentrations (ng/mL) 1, 2.5, 10, 25, 50, 1, 2.5, 10, 25, 50, 10,
25, 100, 250, 500, 100, 150, 200 100, 150, 200 1000, 1500, 2000 QC
Concentrations (ng/mL) 1.5, 60, 140 1.5, 60, 140 30, 600, 1400
Linearity (mean r) 0.9994 0.9988 0.9990 Linear Range (ng/mL) 1-200
1-200 10-2000 LOQ (ng/mL) 1.0 1.0 10.0 Intra-day Precision (% CV)*
2.00-7.26 3.04-4.73 4.63-6.02 Intra-day Accuracy (% Actual)*
101.89-103.49 99.56-103.43 99.41-103.59 Inter-day Precision (% CV)*
3.18-7.04 3.73-7.86 4.55-6.17 Inter-day Accuracy (% Actual)*
98.92-102.33 98.70-100.65 97.50-99.26 Recovery (%) 62.92 67.19
78.51 *precision and accuracy results based on QC samples OXM =
oxymorphone 6-OH-OXM = 6-OH-oxymorphone OXM-3-G =
oxymorphone-3-glucuronide
TABLE-US-00031 TABLE 31 Summary of Method Validation Results for
"Total" Oxymorphone and 6-OH-oxymorphone in Urine Parameter OXM
6-OH-OXM Standard Cons. (ng/mL) 2, 5, 20, 50, 100, 2, 5, 20, 50,
100, 200, 300, 400 200, 300, 400 QC Conc. (ng/mL) 6, 140, 280 6,
140, 280 Linearity (mean r) 0.9983 0.9987 Linear Range (ng/mL)
2-400 2-400 LOQ (ng/mL) 2.0 2.0 Intra-day Precision (% CV)*
2.81-5.58 2.05-4.91 Intra-day Accuracy (% Actual)* 100.23-102.01
101.66-106.02 Inter-day Precision (% CV)* 3.28-6.49 5.38-7.98
Inter-day Accuracy (% Actual)* 96.92-101.76 99.99-103.75 Recovery
85.76 31.14 *precision and accuracy results based on QC samples OXM
= oxymorphone 6-OH-OXM = 6-OH-oxymorphone OXM-3-G =
oxymorphone-3-glucuronide
[0218] Pharmacokinetic and Statistical Methods
[0219] This was a parallel group trial designed to enroll 12
subjects with chronic hepatic impairment due to cirrhosis and 12
healthy control subjects matched for gender and age.
[0220] Samples of venous blood were obtained in a 7 mL EDTA tube
just prior to dose administration (time 0), and at 0.5, 1.0, 1.5,
2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 18.0, 24.0, 30.0, 36.0,
48.0, 60.0, 72.0, 84.0, 96.0, 108.0, and 120 hours after dose
administration.
[0221] Urine samples were obtained for 120 hours after dose
administration. Subjects were to be instructed to void just prior
to administration of the test medication (time 0) and all urine was
collected during the intervals of 0-12, 12-24, 24-48, 48-72, 72-96,
and 96-120 hours after administration of the test medication.
[0222] Calculation of Pharmacokinetic Variables
[0223] Pharmacokinetic parameters were calculated using
model-independent methods. The definitions and methods of
calculation are summarized in the following table:
TABLE-US-00032 TABLE 32 Defination of Pharmacokinetic Variables
Variable Defination C.sub.max Maximum plasma concentration; the
highest concentration observed during a dosage interval. T.sub.max
The time that C.sub.max was observed. C.sub.t The last measured
plasma concentration; the last concentration above the lower limit
of quantitation) following a dose. .lamda..sub.z(Ke) The terminal
elimination rate constant; calculated using linear regression on
the terminal portion of the Ln-concentration versus time curve.
T1/2 Terminal elimination half-life; calculated as
0.693/.lamda..sub.z. AUCT Area under the concentration versus time
curve from time 0 to the last measured concentration (C.sub.t);
calculated using the trapezoidal rule. AUC Area under the
concentration versus time curve from time 0 to infinity; calculated
as AUCT + C.sub.t/.lamda..sub.z. CL Total systemic clearence
(following i.v. administration); calulated as Dose (i.v.)/AUC.
CL/F.sub.o Oral clearence; calculated as Dose (p.o)/AUC.
[0224] Statistical Methods
[0225] All pharmacokinetic results are summarized using appropriate
descriptive statistics. Following log-transformation (natural log),
AUC, AUCT, C.sub.max and .lamda..sub.z results were be compared
between treatment groups using a 90% confidence interval approach.
One-way ANOVA was conducted using the model PKVAR=group, where
group was mild hepatic impairment, moderate-severe hepatic
impairment, or healthy control. Point estimates of the impaired
versus control group differences and the corresponding 90%
confidence limits were constructed. The relationship between
measures of hepatic disease (e.g., serum albumin, bilirubin,
prothrombin time) and oxymorphone oral clearance was explored.
[0226] The frequency of adverse experiences (AEs) were tabulated by
MedDRA term and body system. The incidence of AEs is compared
across treatment groups using an appropriate non-parametric
statistic. The maximum intensity and frequency of AEs are
summarized by treatment group. A new-onset AE is defined as an AE
that was not present prior to treatment with study medication but
appeared following treatment, or was present at treatment
initiation but worsened during treatment. An AE that was present at
treatment initiation but resolved and then reappeared while the
patient was on treatment is a new-onset AE (regardless of the
intensity of the AE when the treatment was initiated).
[0227] All vital sign measurements are summarized by mean values
and changes from baseline. Changes from baseline were be analyzed
across treatment groups using an appropriate parametric
statistic.
[0228] Results
[0229] Disposition of Subjects
[0230] Twenty-four (24) participants, 12 healthy, and 12
hepatically impaired were enrolled and received treatment; all 24
completed the trial. The study population consisted of 16 men and 8
women ranging from 44 to 73 years of age. The hepatically impaired
group included 6 subjects in Child-Pugh Class A, 5 subjects in
Child-Pugh Class B, and 1 subject in Child-Pugh Class C. Within
this report, subjects with hepatic impairment are classified as
having "mild" impairment (Child-Pugh Class A) or "moderate-severe"
impairment (Child-Pugh Class B and C). All three treatment groups
were well matched for age, gender, height, and body weight (Table
33).
TABLE-US-00033 TABLE 33 Summary of Demographic Characteristics
Moderate-Serve Mild Impairment Impairment Healthy Controls Number 6
6 12 Males 4 4 8 Females 2 2 4 Age (years) 55.3 (3.96) 52.5 (4.51)
54.4 (2.53) Height (in) 66.3 (1.74) 65.8 (1.35) 65.7 (1.05) Weight
(Ibs) 175.5 (13.7) 177.2 (14.4) 168.1 (7.45) Mean (SE)
[0231] Protocol Deviations
[0232] There were no deviations in the collection times for
pharmacokinetic samples. Two (2) subjects with hepatic impairment
and one (1) healthy control (Numbers 001 age 73, 010 age 71, and
013 age 17) received waivers of the age requirement. Three subjects
had clinically insignificant deviations from the laboratory
reference range or protocol criteria at screening and were
admitted. Subject 009 had a baseline hemoglobin value of 9.8 g/dL
(protocol limit was 10 g/dL). Subject 013 had a baseline hemoglobin
value of 11.1 g/dL (lower limit of reference range=11.6 g/dL).
Subject 014 had baseline results for hemoglobin and hematocrit of
12.6 g/dL and 37.9%, respectively (lower limit of reference
range=13.2 g/dL for hemoglobin and 38.5% for hematocrit).
[0233] Results of Pharmacokinetic and Statistical Analyses
[0234] Pharmacokinetics of Oxymorphone and Metabolites in
Plasma
[0235] The average plasma concentrations are plotted in FIG. 11. As
noted in FIG. 11, subjects with hepatic impairment had higher
plasma concentrations of oxymorphone and 6-OH-oxymorphone than
healthy controls (matched for age, gender, and weight). The average
plasma concentrations of oxymorphone-3-glucuronide were similar in
all three treatment groups. The average oxymorphone and
6-OH-oxymorphone concentrations in subjects with moderate-severe
hepatic impairment significantly exceeded those of both the healthy
controls and subjects with mild hepatic impairment. The relative
difference between the treatment groups was higher for oxymorphone
than for 6-OH-oxymorphone.
[0236] Mean (.+-.SD) pharmacokinetic results for oxymorphone,
6-OH-oxymorphone, and oxymorphone-3-glucuronide are summarized by
treatment group in the following table (Table 34).
TABLE-US-00034 TABLE 34 Mean (SD) Plasma Pharmacokinetic Results
Moderate-Severe Analyte Variable Mild Impairment Impairment Healthy
Controls Oxymorphone AUC (ng hr/mL) 32.10 (21.71) 105.57 (108.92)
20.58 (9.02) AUCT (ng hr/mL) 29.96 (21.79) 103.66 (108.86) 17.96
(7.69) C.sub.max (ng/mL) 3.98 (4.06) 9.16 (9.76) 1.73 (0.68)
T.sub.max (hr)* 1.75 (0.5-5.0) 1.5 (0.5-5.0) 3.5 (1.0-12.0)
.lamda..sub.z (hr.sup.-1) 0.0830 (0.0392) 0.0970 (0.0365) 0.0970
(0.0540) T1/2 (hr) 11.82 (9.34) 8.04 (2.90) 9.98 (6.35) CL/F
(L/min) 13.30 (5.81) 7.17 (5.08) 21.15 (13.54) 6-OH-oxymorphone AUC
(ng hr/mL) 17.35 (11.17) 32.12 (19.80) 14.76 (11.51) AUCT (ng
hr/mL) 14.11 (9.73) 29.25 (20.17) 10.80 (9.65) C.sub.max (ng/mL)
1.12 (0.79) 1.78 (1.00) 0.72 (0.32) T.sub.max (hr)* 1.25 (0.5-3.0)
1.75 (1.0-6.0) 1.25 (1.0-4.0) .lamda..sub.z (hr.sup.-1) 0.0545
(0.0269) 0.0632 (0.0303) 0.0532 (0.0356) T1/2 (hr) 17.54 (13.12)
13.87 (8.02) 19.19 (11.75) Oxymorphone-3-glucuronide AUC (ng hr/mL)
2954.1 (1136.2) 2713.9 (1498.6) 2979.6 (896.1) AUCT (ng hr/mL)
2836.7 (1091.9) 2629.3 (1457.8) 2886.8 (883.9) C.sub.max (ng/mL)
274.1 (95.8) 212.0 (100.5) 234.3 (41.7) T.sub.max (hr)* 3.0
(3.0-4.0) 3.5 (3.0-4.0) 3.0 (1.5-4.0) .lamda..sub.z (hr.sup.-1)
0.0974 (0.0367) 0.1075 (0.0435) 0.0859 (0.0264) T1/2 (hr) 8.21
(3.87) 7.40 (2.98) 8.89 (3.00) *median (range)
[0237] The most substantial pharmacokinetic differences between the
treatment groups were observed for the parent compound
(oxymorphone). The mean oxymorphone AUC ranged from 20.58 (9.02) in
the control group to 32.10 (21.71) and 105.57 (108.92) nghr/mL in
subjects with mild and moderate-severe hepatic impairment,
respectively. The AUC results were significantly more variable in
the groups with hepatic impairment than in the healthy control
group. Individual oxymorphone AUC results ranged from 15.35 to
74.84 nghr/mL in subjects with mild impairment; from 24.85 to
250.32 nghr/mL in subjects with moderate-severe impairment; and
from 6.18 to 33.85 nghr/mL in healthy controls. Mild hepatic
impairment was associated with an increase in average oxymorphone
AUC of approximately 1.56-fold relative to controls, while
moderate-severe impairment was associated with an increase of
5.13-fold. The mean oxymorphone "C.sub.max" ranged from 1.73 (0.68)
ng/mL in the control group to 3.98 (4.06) ng/mL and 9.16 (9.76)
ng/mL in subjects with mild and moderate-severe hepatic impairment,
respectively. As with AUC, there was substantial variability in
oxymorphone C.sub.max among subjects with mild impairment (range
0.86 to 11.40 ng/mL) and moderate-severe impairment (range 1.66 to
23.59 ng/mL); C.sub.max in the control group ranged from 0.64 to
2.83 ng/mL.
[0238] The mean plasma AUC results for 6-OH-oxymorphone were also
higher in subjects with mild and moderate-severe hepatic impairment
than in healthy controls. The relative increases in 6-OHoxymorphone
AUC were substantially larger in subjects with moderate-severe
impairment (2.18-fold over control) than in subjects with mild
impairment (1.18-fold over control).
[0239] No large differences in oxymorphone-3-glucuronide
pharmacokinetic results were observed. The elimination rates for
oxymorphone and its metabolites did not appear to be significantly
altered by hepatic impairment.
[0240] The pharmacokinetic results for oxymorphone,
6-OH-oxymorphone, and oxymorphone-3-glucuronide were compared
between treatment groups following log-transformation (natural
log). The results of this analysis are displayed in FIG. 12
(oxymorphone), 13 (6-OH-oxymorphone) and 14
(oxymorphone-3-glucuronide).
[0241] The log-transformed results for the AUC of oxymorphone show
at the 90 percent confidence interval a ratio of about 0.9 to about
2.5 for AUC of the mildly impaired to AUC of a healthy patient, for
example about 0.9, about 1.0, about 1.1, about 1.2, about 1.3,
about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9,
about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, or about
2.5.
[0242] The log-transformed results for the C.sub.max of oxymorphone
show at the 90 percent confidence interval a ratio of about 0.9 to
about 2.7 for C.sub.max of the mildly impaired to C.sub.max of a
healthy patient, for example about for example about 0.9, about
1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about
1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about
2.2, about 2.3, about 2.4, about 2.5, about 2.6, or about 2.7.
[0243] The log-transformed results for the AUC of 6-OH-oxymorphone
show at the 90 percent confidence interval a ratio of about 0.8 to
about 2.3 for AUC of the mildly impaired to AUC of a healthy
patient, for example about 0.8, about 0.9, about 1.0, about 1.1,
about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7,
about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, or about
2.3.
[0244] The log-transformed results for the C.sub.max of
6-OH-oxymorphone show at the 90 percent confidence interval a ratio
of about 0.9 to about 2.1 for C.sub.max of the mildly impaired to
C.sub.max of a healthy patient, for example about for example about
0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about
1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, or
about 2.1.
[0245] Relative to healthy controls, oxymorphone AUC was increased
1.52-fold in subjects with mild hepatic impairment and 3.61-fold in
subjects with moderate-to-severe hepatic impairment. The mean
oxymorphone C.sub.max was increased by 1.68- and 3.41-fold in
subjects with mild and moderate-severe impairment, respectively.
The results indicate that the relative bioavailability of
oxymorphone is significantly increased in hepatic impairment. The
amount of increase in oxymorphone bioavailability is substantially
higher in subjects with moderate-severe impairment than in subjects
with mild impairment.
[0246] Examination of individual AUC results indicate that the
observed AUC values for three (3) of the six (6) subjects with mild
hepatic impairment fall within the range observed in the healthy
control group. Although the lower 90% confidence limits for AUC and
C.sub.max in the group with mild hepatic impairment overlap 1.0,
the point estimates exceed the control group by 50% and individual
results indicate that most of the overlap occurs in the upper range
of values observed within the control group.
[0247] The oxymorphone elimination rate constant was slightly
reduced in subjects with mild impairment (ratio=0.87, 90%
confidence limits=0.58-1.31) and slightly increased in subjects
with moderate-severe impairment (ratio=1.11, 90% confidence
limits=0.74-1.66). It is not clear whether the results demonstrate
a real difference from healthy controls, but the lack of
consistency in the direction of change suggests that there are no
clinically significant differences.
[0248] The 6-OH-oxymorphone AUC and C.sub.max in subjects with
moderate-severe hepatic impairment was increased 2.35-fold relative
to the control group. In subjects with mild hepatic impairment the
AUC and C.sub.max were increased by 1.36- and 1.40-fold,
respectively. Examination of individual AUC and C.sub.max results
for subjects with mild hepatic impairment indicates that there is
substantial overlap with the upper half of the control group.
[0249] The results for oxymorphone-3-glucuronide (FIG. 4) AUC and
"C.sub.max" indicate that there is very little difference between
subjects with mild hepatic impairment and healthy controls; the
point estimates were 0.972 and 1.133 for AUC and C.sub.max,
respectively. The AUC and C.sub.max results in subjects with
moderate-severe impairment were approximately 80% of control.
[0250] In order to further examine the metabolism of oxymorphone in
subjects with hepatic impairment, the AUC values were converted to
molar concentrations and the ratios of metabolite-to-parent were
calculated. The results are summarized in FIG. 15.
[0251] The ratio of 6-OH-oxymorphone:oxymorphone and
oxymorphone-3-glucuronide:oxymorphone decreased in association with
the degree of hepatic impairment. The mean (.+-.SD) ratios for
6-OH-oxymorphone:oxymorphone were 0.66 (0.30), 0.55 (0.10), and
0.49 (0.37) in controls and subjects with mild and moderate-severe
impairment, respectively. Although the AUC for 6-OH-oxymorphone
appears to be increased in subjects with hepatic impairment, the
metabolite ratios suggest that liver disease is associated with a
small reduction the conversion of oxymorphone to 6-OH-oxymorphone.
Based on mean results, the conversion of oxymorphone to
6-OH-oxymorphone appears to be reduced by approximately 17% and 26%
in subjects with mild and moderate-severe hepatic impairment,
respectively.
[0252] The mean (.+-.SD) ratios for
oxymorphone-3-glucuronide:oxymorphone were 104.1 (39.5), 67.2
(27.0), and 45.52 (39.2) in controls and subjects with mild and
moderate-severe impairment, respectively. While the plasma AUC's
for oxymorphone-3-glucuronide did not significantly differ between
the three treatment groups, circulating amounts of the
3-glucuronide were substantially reduced relative to the parent
compound. The circulating concentrations of
oxymorphone-3-glucuronide exceed those of the parent compound by
approximately 100-fold in the healthy control group, but by only
45-fold in subjects with moderate-severe impairment. The mean
metabolite ratios suggest that conversion of oxymorphone to
oxymorphone-3-glucuronide is reduced by approximately 35% and 56%
in subjects with mild and moderate-severe hepatic impairment,
respectively.
[0253] Pharmacokinetics of Oxymorphone and Metabolites in Urine
[0254] The concentration of oxymorphone, 6-OH-oxymorphone, and
oxymorphone-3-glucuronide was measured in urine samples collected
from the time of dose administration through 120 hours after dose
administration. In addition to the direct metabolite assays, the
concentrations of oxymorphone and 6-O-Hoxymorphone were measured in
urine samples after hydrolysis with .beta.-glucuronidase. The
results obtained prior to hydrolysis were subtracted from the
results obtained after hydrolysis to provide an indirect measure of
oxymorphone and 6-OH-oxymorphone conjugates. Examination of these
results indicates that oxymorphone-3-glucuronide appears to account
for virtually all of the oxymorphone conjugates. The results
further indicate that glucuronide conjugates of the 6-OH metabolite
are present in the urine. The position of conjugation cannot be
determined from this assay, but it appears that conjugates of
6-OH-oxymorphone are present in higher amounts than the
unconjugated form of the metabolite.
[0255] The cumulative amount of oxymorphone, 6-OH-oxymorphone, and
oxymorphone-3-glucuronide excreted in the urine is displayed in the
graphs of FIG. 16.
[0256] Moderate-severe hepatic impairment was associated with an
approximately 8-fold increase in the amount of oxymorphone excreted
in the urine. The mean amount of oxymorphone excreted unchanged in
the urine was 0.5%, 1.2%, and 4.1% in the control group and in
subjects with mild or moderate-severe hepatic impairment,
respectively. Consistent with the plasma AUC results, subjects with
hepatic impairment excreted a higher amount of 6-OHoxymorphone in
the urine than the controls. The mean amount of 6-OH-oxymorphone
excreted in the urine was 0.25%, 0.71%, and 0.88% in the control
group and in subjects with mild or moderate-severe hepatic
impairment, respectively. The mean amount of
oxymorphone-3-glucuronide excreted in the urine was 38.1%, 39.3%,
and 33.7% in the control group and in subjects with mild or
moderate-severe hepatic impairment, respectively.
[0257] The ratio of metabolite-to-parent excreted in the urine
followed a pattern very similar to that seen in the plasma.
Although the percent of administered dose excreted in the urine as
oxymorphone-3-glucuronide is similar in the three treatment groups,
the amount of metabolite excreted relative to the amount of
oxymorphone excreted unchanged was substantially different. The
mean ratio of oxymorphone-3-glucuronide:oxymorphone excreted in the
urine was 79.05, 39.43, and 33.76 in healthy controls and subjects
with mild or moderate-severe hepatic impairment, respectively. If
the route of excretion for the metabolite is unchanged, the results
indicate that conversion of oxymorphone to
oxymorphone-3-glucuronide is reduced by approximately 50% and 57%
in mild and moderate-severe hepatic impairment, respectively. The
similarity in urinary excretion rates between the three groups
(FIG. 17), suggests that renal excretion is unaffected by liver
disease.
[0258] Urinary excretion of unchanged oxymorphone was essentially
complete by the end of the 48 to 72 hour collection interval;
urinary excretion of 6-OH-oxymorphone was essentially complete by
96 hours; and only small amounts of oxymorphone-3-glucuronide were
excreted during the 96 to 120 hour collection interval.
[0259] Urinary excretion rate constants for oxymorphone and its
metabolites were slightly higher in subjects with hepatic
impairment than in controls, but there were no clinically
meaningful differences in urinary excretion rates. As suggested in
FIG. 17 (i.e., the urinary excretion rate plots are essentially
parallel), these results for mean urinary excretion rate constants
indicate that urinary excretion is not impaired in this population
with hepatic disease. This data supports a conclusion that the
metabolic ratios are reflecting differences in the degree of
impairment in oxymorphone metabolism rather than differential
excretion rates.
[0260] Relationship Between Oxymorphone Oral Clearance and Measures
of Hepatic Function
[0261] The potential relationship between oxymorphone clearance and
potential indicators of hepatic impairment was explored by the use
of scatter plots (FIG. 18) and tests of association.
[0262] As reflected in the prior pharmacokinetic analyses, the oral
clearance of oxymorphone differed significantly between the three
treatment groups (p=0.0112). A nonparametric correlation analysis
indicated that there were statistically significant correlations
between oxymorphone oral clearance and prothrombin time, serum
albumin, SGOT, and LDH. However, as indicated in FIG. 18, none of
these relationships were particularly strong.
[0263] The hepatically impaired subjects with the most extreme
oxymorphone pharmacokinetic results are summarized in the following
table (Table 35).
TABLE-US-00035 TABLE 35 Characteristics of Subjects with Very Low
Oxymorphone Clearance Values CL/F AUC Cmax Albumin SGOT LDH
Bilirubin PT Subject (L/min) (ng hr/mL) (ng/mL) (g/dL) (IU/L)
(IU/L) (mg/dL) (sec) 006 (B)* 7.34 45.40 4.31 4.3 262 215 1.4 17.7
007 (A)* 4.45 74.84 11.40 4.1 35 150 0.7 10.1 009 (B)* 1.38 241.14
19.57 3.4 25 189 2.4 11.1 010 (B)* 7.63 43.67 3.72 3.7 26 135 1.2
9.6 011 (C)* 1.33 250.32 23.59 2.2 102 242 6.1 17.1 *Child-Pugh
Class PT = prothrombin time
[0264] Mean oxymorphone oral clearance in the control group was
21.15 L/min (range 9.85 to 53.97 L/min). Five (5) subjects with
hepatic impairment (Subjects 006, 007, 009, 010, and 011) had very
low oral clearance values which were well below the lower end of
the healthy control group; and also had significantly elevated
oxymorphone AUC and C.sub.max values (Table 35). One of these
subjects was in Child-Pugh Class A (Subject 007), three were in
Child-Pugh Class B (Subjects 006, 009, and 010), and one was in
Child-Pugh Class C (Subject 011). While some general correlation
was present for SGOT and LDH, elevations in hepatic enzymes does
not appear to be a good predictor of substantial changes in
oxymorphone clearance since most of these subjects had results
within the normal range. The two subjects with the lowest
oxymorphone clearances (Subjects 009 and 011) both had low serum
albumin concentrations (3.4 and 2.2 g/dL, respectively), elevated
serum bilirubin levels (2.4 and 6.1 mg/dL, respectively), and
prothrombin times above the upper limit of normal (11.1 and 17.1
sec, respectively).
[0265] Discussion
[0266] Following oral administration, oxymorphone is subjected to
extensive first-pass metabolism, is highly metabolized, and can be
categorized as a highly extracted drug. Following administration of
an oral solution, oxymorphone has been shown to have an average
absolute bioavailability of approximately 10%. Less than 1% of the
administered dose is excreted unchanged in the urine. Oxymorphone
bioavailability following administration of EN3202 tablets is
equivalent to an oral solution; indicating that slowing the rate of
oxymorphone delivery reduces the peak plasma concentrations but
does not change the absolute bioavailability. Due to the fact that
oxymorphone is a highly extracted drug and subject to a high degree
of first pass metabolism, a significant increase in oxymorphone
bioavailability can be expected in patients with impaired hepatic
function.
[0267] Within the current trial, the mean (.+-.SD) oxymorphone AUC
and C.sub.max values in healthy control subjects were 20.58 (9.02)
nghr/mL and 1.73 (0.68) ng/mL, respectively. The corresponding
values for AUC and C.sub.max in subjects with hepatic disease were
32.10 (21.71) nghr/mL and 3.98 (4.06) ng/mL in subjects with mild
disease, and 105.57 (108.92) nghr/mL and 9.16 (9.76) ng/mL in
subjects with moderate or severe disease. Individual oxymorphone
AUC values varied across a 5-fold range (6.2 to 33.9 nghr/mL) in
healthy controls, a 5-fold range (15.4 to 74.8 nghr/mL) in subjects
with mild disease, and a 10-fold range (24.9 to 250.3 nghr/mL) in
subjects with moderate-severe disease.
[0268] There was not much difference in the median oxymorphone AUC
between the mildly-impaired group (24.7 nghr/mL) and the control
group (23.8 ng/mL). Only one of six subjects in this group (Subject
007, AUC=74.84 nghr/mL) had an oxymorphone AUC value outside the
range observed in healthy subjects. As a result, the relative
difference in mean AUC between the mild group and the control group
(mean ratio=1.52) is substantially due to one subject and probably
overestimates the effect for the majority of subjects with mild
liver disease. The mean oxymorphone AUC for the mild group, after
excluding Subject 007, is only 23.55 nghr/mL.
[0269] The mean bioavailability of oxymorphone was increased
3,6-fold (90% confidence interval 2.4 to 6.6) in subjects with
moderate or severe liver disease relative to healthy controls. Two
subjects in this group had very high oxymorphone plasma levels
relative to controls; one was Child-Pugh Class C (Subject 011,
AUC=250.32 nghr/mL and C.sub.max=23.59 ng/mL) and the other was
Child-Pugh Class B (Subject 009, AUC=241.14 nghr/mL and
C.sub.max=19.57 ng/mL). Two of the remaining subjects with moderate
hepatic impairment had AUC values, which were essentially twice the
mean of the control group, and the other two subjects in the group
had AUC values, which were within the upper range of control.
[0270] As reported in a previous study, the average absolute
bioavailability of orally administered oxymorphone is approximately
10%. As a result, complete elimination of first-pass metabolism
(i.e., increasing absolute bioavailability from 10% to 100%) could
be expected to result in a 10-fold increase in oxymorphone AUC.
Changes of this magnitude have been observed in one subject with
moderate and one subject with severe liver disease. While the oral
bioavailability of oxymorphone was clearly increased in subjects
with moderate or severe liver disease, this change was not
associated with increases in the plasma elimination half-life for
oxymorphone, 6-OH-oxymorphone, or oxymorphone-3-glucuronide. Even
in association with apparent 10-fold increases in oxymorphone
bioavailability, the plasma oxymorphone elimination half-life was
6.96 hours and 10.67 hours, in Subjects 009 and 011, respectively.
Considering these factors, it appears reasonable to conclude that
results at or near the maximal level of oxymorphone bioavailability
have been observed in the present study.
[0271] The mean plasma AUC and C.sub.max for 6-OH-oxymorphone was
increased approximately 2,3-fold relative to the healthy control
group in subjects with moderate or severe hepatic impairment. Mean
plasma concentrations of oxymorphone-3-glucuronide did not differ
significantly between the three treatment groups. However, plasma
and urine metabolite ratios indicate that the conversion of
oxymorphone to oxymorphone-3-glucuronide is significantly impaired
in the group with moderate-severe liver disease. The mean
metabolite-to-parent ratios for oxymorphone-3-glucuronide, in both
plasma and urine, were 2,3-fold lower in subjects with
moderate-severe impairment than in the control group. Conversion of
oxymorphone to 6-OH-oxymorphone appears to be reduced in subjects
with moderate-severe impairment, but to a lesser extent than
conversion to the 3-glucuronide.
[0272] While there was no single good predictor of oxymorphone
clearance, the two subjects with the lowest oxymorphone clearances
(Subjects 009 and 011) both had low serum albumin concentrations
(3.4 and 2.2 g/dL, respectively), elevated serum bilirubin levels
(2.4 and 6.1 mg/dL, respectively), and prothrombin times above the
upper limit of normal (11.1 and 17.1 sec, respectively).
[0273] The results of this study demonstrate that moderate or
severe hepatic impairment (Child-Pugh Class B or C) is associated
with a significant increase in oxymorphone bioavailability and a
reduction in the conversion of oxymorphone to both 6-OH-oxymorphone
and oxymorphone-3-glucuronide. Subjects with moderate or severe
liver disease may have clinically significant increases in plasma
oxymorphone concentrations; mean oxymorphone AUC was increased
3,6-fold for the group as a whole, and up to 10-fold in two of six
individual subjects. The majority of subjects with mild liver
disease (Child-Pugh Class A) do not appear to have a significant
increase in oxymorphone bioavailability relative to healthy
controls. Since oxymorphone is subject to high first-pass
metabolism and these results have confirmed increased
bioavailability, particularly in moderate-severe hepatically
impaired patients, caution should be exercised in initial dosing
and slow titration of these patients.
[0274] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference there individually and
specifically indicated to be incorporated by reference were set
forth in its entirety herein.
[0275] The use of the terms "a" and "an" and "the" and similar
referents in the context of this disclosure (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods described herein can
be performed in any suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (e.g., such as, preferred,
preferably) provided herein, is intended merely to further
illustrate the content of the disclosure and does not pose a
limitation on the scope of the claims. No language in the
specification should be construed as indicating any non-claimed
element as essential to the practice of the invention.
[0276] Alternative embodiments of the claimed invention are
described herein, including the best mode known to the inventors
for carrying out the claimed invention. Of these, variations of the
disclosed embodiments will become apparent to those of ordinary
skill in the art upon reading the foregoing disclosure. The
inventors expect skilled artisans to employ such variations as
appropriate, and the inventors intend for the invention to be
practiced otherwise than as specifically described herein.
[0277] Accordingly, this invention includes all modifications and
equivalents of the subject matter recited in the claims appended
hereto as permitted by applicable law. Moreover, any combination of
the above described elements in all possible variations thereof is
encompassed by the invention unless otherwise indicated herein or
otherwise clearly contradicted by context.
[0278] The use of individual numerical values are stated as
approximations as though the values were preceded by the word
"about" or "approximately." Similarly, the numerical values in the
various ranges specified in this application, unless expressly
indicated otherwise, are stated as approximations as though the
minimum and maximum values within the stated ranges were both
preceded by the word "about" or "approximately." In this manner,
variations above and below the stated ranges can be used to achieve
substantially the same results as values within the ranges. As used
herein, the terms "about" and "approximately" when referring to a
numerical value shall have their plain and ordinary meanings to a
person of ordinary skill in the art to which the claimed subject
matter is most closely related or the art relevant to the range or
element at issue. The amount of broadening from the strict
numerical boundary depends upon many factors. For example, some of
the factors which may be considered include the criticality of the
element and/or the effect a given amount of variation will have on
the performance of the claimed subject matter, as well as other
considerations known to those of skill in the art. As used herein,
the use of differing amounts of significant digits for different
numerical values is not meant to limit how the use of the words
"about" or "approximately" will serve to broaden a particular
numerical value. Thus, as a general matter, "about" or
"approximately" broaden the numerical value. Also, the disclosure
of ranges is intended as a continuous range including every value
between the minimum and maximum values plus the broadening of the
range afforded by the use of the term "about" or "approximately".
Thus, recitation of ranges of values herein are merely intended to
serve as a shorthand method of referring individually to each
separate value falling within the range, unless otherwise indicated
herein, and each separate value is incorporated into the
specification as if it were individually recited herein.
* * * * *